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Citation: Sutovska, H.; Babarikova,
K.; Zeman, M.; Molcan, L. Prenatal
Hypoxia Affects Foetal
Cardiovascular Regulatory
Mechanisms in a Sex- and
Circadian-Dependent Manner: A
Review. Int. J. Mol. Sci. 2022,23, 2885.
https://doi.org/10.3390/
ijms23052885
Academic Editors: Elena Rybnikova
and Ludmila D. Lukyanova
Received: 11 February 2022
Accepted: 5 March 2022
Published: 7 March 2022
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International Journal of
Molecular Sciences
Review
Prenatal Hypoxia Affects Foetal Cardiovascular Regulatory
Mechanisms in a Sex- and Circadian-Dependent Manner:
A Review
Hana Sutovska †, Katarina Babarikova †, Michal Zeman * and Lubos Molcan
Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University,
842 15 Bratislava, Slovakia; sutovska6@uniba.sk (H.S.); babarikova3@uniba.sk (K.B.);
lubos.molcan@uniba.sk (L.M.)
*Correspondence: michal.zeman@uniba.sk; Tel.: +421-2-9014-9424
† These authors contributed equally to this work.
Abstract:
Prenatal hypoxia during the prenatal period can interfere with the developmental trajec-
tory and lead to developing hypertension in adulthood. Prenatal hypoxia is often associated with
intrauterine growth restriction that interferes with metabolism and can lead to multilevel changes.
Therefore, we analysed the effects of prenatal hypoxia predominantly not associated with intrauterine
growth restriction using publications up to September 2021. We focused on: (1) The response of car-
diovascular regulatory mechanisms, such as the chemoreflex, adenosine, nitric oxide, and angiotensin
II on prenatal hypoxia. (2) The role of the placenta in causing and attenuating the effects of hypoxia.
(3) Environmental conditions and the mother’s health contribution to the development of prenatal
hypoxia. (4) The sex-dependent effects of prenatal hypoxia on cardiovascular regulatory mechanisms
and the connection between hypoxia-inducible factors and circadian variability. We identified that
the possible relationship between the effects of prenatal hypoxia on the cardiovascular regulatory
mechanism may vary depending on circadian variability and phase of the days. In summary, even
short-term prenatal hypoxia significantly affects cardiovascular regulatory mechanisms and programs
hypertension in adulthood, while prenatal programming effects are not only dependent on the critical
period, and sensitivity can change within circadian oscillations.
Keywords:
prenatal hypoxia; prenatal programming; cardiovascular system; foetus; placenta; circa-
dian variability
1. Introduction
The cardiovascular system is a dynamic system that can adapt to adverse conditions
to maintain and satisfy homeostasis in the organism. Prolonged cardiovascular adapta-
tions can result in the development of hypertension and other cardiovascular diseases
in adulthood; however, hypertension can have its origins in the prenatal period when
the cardiovascular system develops structurally and functionally [
1
]. This phenomenon
observed in animals and humans is described as prenatal programming [2,3].
Prenatal programming is defined as a response to adverse factors acting during a criti-
cal prenatal period, leading to changes in the developmental trajectory with a permanent
effect on the offspring’s adult phenotype [
3
]. Insults during the prenatal period lead to
permanent structural or functional changes of the tissues and organs [
3
]. In general, if the
prenatal factor acts during the early phase of an organ’s development, it leads to structural
defects. In contrast, the action during the later phases of development affects functions [
4
].
The effect of prenatal insults on the foetus depends not only on the developmental stage
but also on the type of insult. Consequently, some types of insults, such as various agents
(warfarin, thalidomide, tetracycline, alcohol) and environmental factors of chemical (toxic
metals), physical (ionising radiation) or biological origin (infection diseases), can disrupt
Int. J. Mol. Sci. 2022,23, 2885. https://doi.org/10.3390/ijms23052885 https://www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2022,23, 2885 2 of 30
the normal in utero development of the foetus and increase the risk of congenital disabilities,
malformations, and in some cases, even death of the developing foetus [5].
Moderate effects on the foetus include high or low food availability, oxygen deficiency
(hypoxia), maternal obesity, inadequate prenatal care, maternal stress, and maternal chronic
diseases. The consequences of these factors can be identified during pregnancy screening
and immediately after birth because they are often associated with a reduction in birth
weight and asymmetric organ growth [
6
]. According to Barker’s theory, neonates with
reduced birth weight have a higher incidence of stroke and coronary heart disease in
adulthood [
7
]. A reduction in birth weight of neonates is the most accessible marker of
poor in utero development. Indeed, many studies have recently explored an association
between intrauterine growth restriction and an increased postnatal risk of cardiovascular
diseases [8–10].
However, prenatal insults do not necessarily have to be manifested by low birth
weight (Table 1) and still can lead to the programming of diseases in adulthood. This
phenomenon is observed after exposure to prenatal hypoxia, which is a common com-
plication in gravidity. In this case, neonates are born seemingly healthy, avoiding the
early screening of diseases; however, due to prenatal hypoxia, the foetus has impaired
endothelial function and undergoes oxidative stress [
2
,
9
,
11
], morphological changes in
the heart and blood vessels [
2
,
12
] and changes in the activity of the autonomic nervous
system [
13
,
14
], which is one of the key factors in the development of hypertension [
15
].
Prenatal hypoxia contributes to the development of hypertension, ischemic heart disease,
coronary heart disease, heart failure, metabolic syndrome, and increased susceptibility to
ischemic injury in humans [16,17].
Table 1. The effect of prenatal hypoxia on birth body weight.
Oxygen Duration; Time Animal Model Birth Body
Weight Ref.
6.5% 1–20 ED; 8 h per day: 80 s hypoxia and 120 s
normoxia; 18 cycles per hour Sprague Dawley rats ↓[18]
7% 13–14 ED; 3 h Wistar rats ↓[19]
7% 18 ED; 3 h Wistar rats = [20]
9% 15–21 ED; 6 h per day Sprague Dawley rats = [21]
9.5–10%
12, 24, 48, 120 h immediately prior to delivery
at term Sprague Dawley rats ↓[22]
10% 5–19 ED Sprague Dawley rats ↓[23]
10% 5–20 ED Sprague Dawley rats ↓[13,24–27]
10% 15–20 ED Wistar rats ↓[28,29]
10% from 121 ED–NA sheep = [30]
10 ±0.5% 5–20 ED Sprague Dawley rats ↓[31]
10.5% 15–20 ED; 4 h per day Sprague Dawley rats = [32]
10.5% 4–21 ED Sprague Dawley rats ↓[33]
10.5% 15–21 ED Sprague Dawley rats ↓[34,35]
10.5% 11–17.5 ED BALB/c mice ↓[36]
10.5% last 15 days of gravidity guinea pigs ↓[37]
10 ±1% 7–21 ED; 3 h per day Sprague Dawley rats ↓[38]
11% 15–21 ED rats ↓[39]
11.5% 13–20 ED Sprague Dawley rats ↓[40]
12% 15–19 ED Sprague Dawley rats = [41]
12% 14.5–21 ED CD-1 mice ↓[11]
Int. J. Mol. Sci. 2022,23, 2885 3 of 30
Table 1. Cont.
Oxygen Duration; Time Animal Model Birth Body
Weight Ref.
13% 6–20 ED Wistar rats = [2,12,42]
13–14% 6–20 ED Wistar rats = [43]
14% 6–18 ED C57BL/J6 mice = [44]
15% 19 ED–delivery; 10 min; 6 times per day Sprague Dawley rats = [45]
NA NA Jackson Black C-57 mice = [46]
280–300 mmHg; 8000 m above sea level
14 ED–delivery; 2 h per day C57BL/6 mice = [47]
PaO213 mmHg 14 days sheep = [48]
3820 m above sea level 30–120 ED sheep = [49]
4000 m above sea level on first day,
5000 m above sea level on the second
to fifth day 14–18 ED, 8 h per day rats ↓[50]
chronic anaemia NA sheep = [51]
9000 m above sea level; PaO2
42 mmHg 14–19 ED, once 4 h albino rats ↓[52]
NA 105–138 ED sheep ↓[53]
ED, embryonic day; NA, non-available;
↓
, decreased birth body weight; =, no changes of the birth body weight in
comparison with control group.
The most important signalling molecules that respond to changes in oxygen content
are hypoxia-inducible factors (HIFs) from the family of heterodimeric transcription factors.
The HIF transcription factor is composed of two subunits,
α
and
β
. Under normoxia,
HIF-1
α
is rapidly degraded, but if the partial pressure of oxygen decreases, it is stabilized
and accumulates in the cells. HIF-1
α
maintains oxygen homeostasis by regulating the
expression of hundreds of genes and interacts with pathways involved in the regulation
of the cardiovascular system, such as the chemoreflex, sympathetic drive [
54
], renin-
angiotensin-aldosterone system (RAAS) [
55
,
56
], and local vessel wall components such as
nitric oxide (NO) [
57
–
59
] and endothelin-1 [
60
,
61
]. Moreover, HIF directly interacts with
the circadian clock because HIF-1
α
controls the expression of several canonical circadian
genes and the response to hypoxia is gated by the circadian clock [
62
]. The relationship
between the HIF and clock can be reciprocal, because in several experimental models,
hypoxia was found to reduce the amplitude of circadian rhythms or their response to phase
shifts [63].
In this review, we analyse the effects of prenatal hypoxia, which is not predominantly
associated with intrauterine growth restriction but leads to changes in blood pressure and
hypertension in adulthood. The effects of intrauterine growth restriction interfere with
metabolism and can lead to multifactorial changes in the development of cardiovascu-
lar regulatory mechanisms and programming blood pressure. In our review, we aim to
describe: (1) The response of cardiovascular regulatory mechanisms, such as the chemore-
flex, adenosine, NO, reactive oxygen species (ROS) and RAAS on prenatal hypoxia and
its effects on hypertension in adulthood. In addition, we describe the effects of prenatal
hypoxia on morphological-functional changes in the heart, vessels, and kidneys, which can
be risk factors for hypertension. (2) The role of the placenta in causing and attenuating
the effects of hypoxia. (3) The availability of oxygen to the foetus can be affected by the
mother’s current health status and environmental conditions, thus, the mother plays a key
role in causing prenatal hypoxia. (4) The sex-dependent effects of prenatal hypoxia on
cardiovascular regulatory mechanisms while also considering the circadian sensitivity of
foetuses to prenatal hypoxia within 24 h.
Int. J. Mol. Sci. 2022,23, 2885 4 of 30
2. Methodology
This review includes publications describing the effects of prenatal hypoxia on foetal
cardiovascular regulatory mechanisms, which are not associated with intrauterine growth
restriction in a sex- and circadian-dependent manner. The literature research was performed
in the PubMed, Scopus and Google Scholar databases, using the following keywords: “pre-
natal hypoxia”, “antenatal hypoxia”, “cardiovascular system”, “blood pressure”, “foetus”,
“prenatal programming”, “chemoreflex”, “adenosine”, “nitric oxide”, “reactive oxygen
species”, “catecholamines”, “angiotensin”, “heart”, “blood vessel”, “kidney”, “sex”, “male”,
“female”, “placenta” and “circadian variability”. Relevant studies were evaluated by title
and abstract, followed by a full-text overview. We analysed the effects of prenatal hypoxia
on cardiovascular regulatory mechanisms predominantly in mice, rats, and sheep. We
present publications (Table 1) that describe the prenatal hypoxia effects on body weight
often independent of intrauterine growth restriction and we included in our review all
papers that were published by September 2021.
3. Prenatal Hypoxia
Prenatal hypoxia is a common complication in pregnancy, developing from various
causes (Figure 1). In gravidity, prenatal hypoxia often occurs as a comorbidity of maternal
diseases, such as hypertension, anaemia and respiratory diseases or as a consequence of
poor maternal lifestyle, such as smoking, so-called preplacental hypoxia. Prenatal hypoxia
can also develop as a consequence of morphological or functional changes in the placenta,
such as failed remodelling of spiral arteries or metabolic reprogramming (uteroplacental
hypoxia). Disturbed fetoplacental perfusion due to changes in foetal circulation or genetic
anomalies in the circulatory system can lead to postplacental hypoxia [64].
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 31
formed in the PubMed, Scopus and Google Scholar databases, using the following key-
words: “prenatal hypoxia”, “antenatal hypoxia”, “cardiovascular system”, “blood pres-
sure”, “foetus”, “prenatal programming”, “chemoreflex”, “adenosine”, “nitric oxide”,
“reactive oxygen species”, “catecholamines”, “angiotensin”, “heart”, “blood vessel”,
“kidney”, “sex”, “male”, “female”, “placenta” and “circadian variability”. Relevant stud-
ies were evaluated by title and abstract, followed by a full-text overview. We analysed the
effects of prenatal hypoxia on cardiovascular regulatory mechanisms predominantly in
mice, rats, and sheep. We present publications (Table 1) that describe the prenatal hypoxia
effects on body weight often independent of intrauterine growth restriction and we in-
cluded in our review all papers that were published by September 2021.
3. Prenatal Hypoxia
Prenatal hypoxia is a common complication in pregnancy, developing from various
causes (Figure 1). In gravidity, prenatal hypoxia often occurs as a comorbidity of maternal
diseases, such as hypertension, anaemia and respiratory diseases or as a consequence of
poor maternal lifestyle, such as smoking, so-called preplacental hypoxia. Prenatal hypoxia
can also develop as a consequence of morphological or functional changes in the placenta,
such as failed remodelling of spiral arteries or metabolic reprogramming (uteroplacental
hypoxia). Disturbed fetoplacental perfusion due to changes in foetal circulation or genetic
anomalies in the circulatory system can lead to postplacental hypoxia [64].
Figure 1. Prenatal hypoxia as result of mother, placenta, and foetus and their effects on cardiovas-
cular regulatory mechanisms in the foetus. Based on the level in which prenatal hypoxia occurs, it
can be divided into preplacental hypoxia, uteroplacental hypoxia, and postplacental hypoxia. The
foetus is able to compensate for oxygen deficiency and maintain homeostasis by the activation of
regulatory mechanisms. The response of the foetus to prenatal hypoxia can also be modulated by
Figure 1.
Prenatal hypoxia as result of mother, placenta, and foetus and their effects on cardiovascular
regulatory mechanisms in the foetus. Based on the level in which prenatal hypoxia occurs, it can be
Int. J. Mol. Sci. 2022,23, 2885 5 of 30
divided into preplacental hypoxia, uteroplacental hypoxia, and postplacental hypoxia. The foetus is
able to compensate for oxygen deficiency and maintain homeostasis by the activation of regulatory
mechanisms. The response of the foetus to prenatal hypoxia can also be modulated by the placenta
and the mother. Changes in the set points of the cardiovascular regulatory mechanisms in the foetus
increase susceptibility to hypertension in adulthood.
3.1. Foetus
Foetal blood is hypoxic compared with maternal blood. The foetal partial pressure
of oxygen is reduced to 20–30 mmHg, while in the mother, the arterial partial pressure
of oxygen is about 75–100 mmHg at sea level [
65
–
67
]. Nevertheless, the foetus can cope
with up to a 50% (10–15 mmHg) reduction of the partial pressure of oxygen [68]. This has
been well-described in sheep used as a common animal model of prenatal hypoxia. In
sheep, during normoxia, the maternal partial pressure of oxygen is about 100 mmHg. In
comparison, during hypoxia, it can decrease up to 35 mmHg, and the foetus can compensate
for this condition. In the case of a sheep foetus, due to hypoxia, the oxygen saturation
can decrease from 20 mmHg to 10.5 mmHg in the umbilical artery and from 34 mmHg
to 15 mmHg in the umbilical vein [
69
]. A decrease of the partial pressure of oxygen in
the foetus causes femoral vasoconstriction because of local and neurohumoral regulatory
mechanisms [70], which can cooperate with the foetal, placental, or maternal regulations.
The adaptive response to hypoxia is a combination of the following five factors:
(1)
Reflex response mediated by the chemoreflex and
α1
-adrenergic signalling in pe-
ripheral vessels [
70
–
72
]. Hypoxia also directly affects chromaffin cells in the adrenal
medulla, thereby stimulating the release of catecholamines. Chromaffin cells of the
adrenal medulla have a chemosensitive function until a sympathetic innervation
develops between the adrenal glands and the central nervous system [73].
(2)
An endocrine response that is involved in maintaining peripheral vasoconstriction
and is activated within about 15 min of the onset of hypoxia, including angiotensin II
(Ang II) and other vasoactive substances [71,74,75].
(3)
Local components that respond to the direct effect of hypoxia at the tissue level. The
vascular endothelium acts as a hypoxic sensor but also an effector system that releases
NO [
76
], adenosine [
77
], and endothelin-1 [
78
], thus affecting the function of vascular
smooth muscle.
(4)
Placental vasoactive substances are released from the placenta into the foetus and can
thus modulate the response to hypoxia. Such substances include adenosine [
79
], Ang
II, thromboxane, endothelin, NO [80], glucocorticoids and others [81].
(5)
Maternal factors that pass from the mother to the foetus. Environmental hypoxia,
during which both the mother and the foetus are hypoxic, causes adaptive changes not
only at the level of the foetus but also in the mother. Some of the mother’s adaptation
mechanisms may also affect foetal development [81].
Activation of the described mechanisms as a response to prenatal hypoxia ensures
sufficient blood flow to vital organs, such as the brain and heart, by peripheral vasocon-
striction and reduction in oxygen consumption by the tissues and organs. We further
describe the effects of prenatal hypoxia on cardiovascular regulatory mechanisms: the
chemoreflex, adenosine, NO, ROS, and RAAS, as well as the effects of prenatal hypoxia on
morphological-functional changes in the heart, blood vessels, and kidneys (Table 2).
Int. J. Mol. Sci. 2022,23, 2885 6 of 30
Table 2. Effects of prenatal hypoxia on the regulatory mechanism of blood pressure.
Prenatal Hypoxia Type Animal Model Hypoxia Outcomes Ref.
Adenosine
Arterial PaO215 mmHg; 1 h Sheep Foetal acidosis, mean arterial pressure
increase, a transient heart rate decrease [77]
Hypoxia/anoxia;
20 or 60 min
A1R+/+, A1R+/−and A1R−/−
C57BL mice, hippocampal
slices, isolated brainstem
spinal cord
Reduction in field excitatory
postsynaptic potential [82]
10% O2;
7.5–10.5 ED A1AR+/+ and A1AR-deficient
C57BL/6 mice
Growth retardation, less stabilized HIF-1
α
protein and cardiac gene expression in
A1AR−/−embryos
[83]
10–12% O2; 30 min;
122–128 ED Western sheep
Cortical blood flow increase, attenuated
by a non-selective adenosine
receptor antagonist
[84]
NO, ROS
13% O2;
6–20 ED Wistar rats
Foetus: aortic thickening, enhanced
nitrotyrosine staining and increased
cardiac HSP70 expression.
Adult offspring: impaired NO-dependent
relaxation, increased
myocardial contractility
[2]
12% O2; for 4, 7, or 10 days;
58–62 ED Hartley-Duncan guinea pigs
Increased eNOS mRNA in foetal
ventricles, not altered K+-channel
activation in response to
acetylcholine-stimulated coronary dilation
[59]
40–50% uteroplacental artery
ligation; 25 ED New Zealand white rabbits
Normal left and right ventricular
thickness, increased vessel dilatation;
HIF-1α, eNOS, p-eNOS, and iNOS
induction suggesting increased NO and
oxidative stress in the hearts
[85]
13% O2; most of gestation
(prior to day 5) Wistar rats
Maternal and placental oxidative
stress—prevented by maternal treatment
with vitamin C
[42]
13% O2; 6–20 ED Wistar rats Increased LF/HF HRV ratio and
baroreflex gain—prevented by vitamin C [86]
Acute: 10% O2; 0.5 h,
127 ±1 ED; chronic: 10% O2;
105–138 ED
Welsh Mountain sheep
Mitochondria-derived oxidative stress,
endothelial dysfunction and hypertension
in adult offspring
[53]
6% O2; 0.5 h Welsh Mountain sheep
Increased redistribution of blood flow and
the glycemic and plasma
catecholamine responses
[87]
14 ±0.5% O2;
1–19 ED (embryos
underwent euthanasia)
Bovans Brown eggs
Cardiac systolic dysfunction, impaired
cardiac contractility and relaxability,
increased cardiac sympathetic dominance,
endothelial dysfunction in
peripheral circulations
[88]
Conceived, gestated, born
and studied at Putre
Research Station (3600 m
above sea level)
Sheep (neonates)
Worsened carotid blood flow, vascular
responses to potassium, serotonin,
methacholine, and melatonin; diminished
endothelial response via NO-independent
mechanisms in isolated arteries
[89]
10.5% O2; 15–21 ED Sprague Dawley rats Revealed reprogramming of
the mitochondrion [90]
Int. J. Mol. Sci. 2022,23, 2885 7 of 30
Table 2. Cont.
Prenatal Hypoxia Type Animal Model Hypoxia Outcomes Ref.
11% O2;
15–21 ED Sprague Dawley rats
Male and female foetuses: increased
oxidative stress in placentas; 7-month-old
male and female offspring: cardiac
diastolic dysfunction; 13-month-old
female offspring: reduced vascular
sensitivity to methacholine, 13-month-old
male offspring: decreased vascular
sensitivity to phenylephrine
[91]
13–14% O2;
6–20 ED Wistar rats
Increased α1-adrenergic reactivity of the
cardiovascular system, enhanced reactive
hyperemia, sympathetic dominance,
hypercontractility and diastolic
dysfunction in the heart
[92]
7% O2; 2 h; 50–55 ED; foetal
hearts were harvested at the
end of hypoxia
Guinea pigs
Decreased heart ATP, lipid peroxides,
4-hydroxynonenal and malondialdehyde;
increased apoptotic index, unremarkable
foetal heart morphology, normal
postpartum neonatal cardiac function and
cerebral histology
[93]
Acute: 220–240 mmHg;
10,000 m above sea level;
4–5 min; 18 ED–delivery;
chronic: 280–300 mmHg;
8000 m above sea level); 2 h;
14 ED–delivery
C57BL/6 mice
Acute hypoxia: decreased basal O2
consumption rate and intensity of
oxidative phosphorylation by the brain
mitochondria of newborn, the activation
of the respiratory complex II; chronic
hypoxia: increased basal O
2
consumption
rate and oxidative
phosphorylation intensity
[47]
RAAS
10.5% O2;
6–21 ED Sprague Dawley rats
Foetal growth restriction, impaired
trophoblast invasion and uteroplacental
vascular remodeling, increased plasma
ET-1 levels, prepro-ET-1 mRNA, ET-1 type
A receptor and AT
1
receptor in the kidney
and placenta
[78]
12% O2;
from 14.5 ED CD1 mice
Weaning: both sexes: increased
susceptibility to salt-induced cardiac
fibrosis; male: renal fibrosis by high salt,
increased renal renin mRNA;
12 months: both sexes: increased renal
renin mRNA expression and
concentrations, male: increased AT1a
mRNA expression
[94]
10.5% O2;
4–21 ED Sprague Dawley rats
Increased superoxide production and
decreased SOD expression, enhanced
NADPH4, but not NADPH1 or NADPH2
in foetal aortas; increased Ang
II-mediated vessel contractions in foetal
thoracic aortas blocked by losartan
[33]
Acute isocapnic hypoxaemia
(foetal PaO212–14 mmHg);
1 h; 110/114–124/128 ED
Sheep foetuses
No effects in foetal heart rate, mean
arterial pressure, baro- or chemoreflexes,
femoral blood flow, femoral vascular
resistance or foetal growth
[48]
Int. J. Mol. Sci. 2022,23, 2885 8 of 30
Table 2. Cont.
Prenatal Hypoxia Type Animal Model Hypoxia Outcomes Ref.
Reflex
Aortic PaO212–15 mmHg
without alterations in foetal
PaCO2; 1 h; 124 ED
Welsh Mountain
sheep foetuses
Transient bradycardia, femoral
vasoconstriction and increases in plasma
noradrenaline and adrenaline; the NO
clamp: persisted bradycardia, greater
peripheral vasoconstrictor and
catecholaminergic responses—enhanced
the chemoreflex sensitivity
[70]
PaO215 mmHg;
137–144 ED
Border Leicester Merino
cross sheep Reduced and delayed the IA-type current [73]
Aortic PaO210–11 mmHg
without alterations in foetal
PaCO2; 1 h; 117–118 ED
Sheep foetuses
Bradycardia, increased arterial blood
pressure, femoral vasoconstriction, blood
glucose, lactate concentrations, plasma
epinephrine and norepinephrine
[95]
Foetal arterial oxygen
saturation by 47.3% (uterine
blood flow restriction);
118–126 ED
Sheep foetuses
Bradycardia, not in denervated foetuses,
followed by a tachycardia; increased
foetal heart rate in denervated foetuses;
transiently increased foetal blood pressure
in intact foetuses and decrease in
denervated foetuses; increased cerebral
blood flow in both intact and denervated
foetuses; decreased carotid vascular
resistance in denervated foetuses
[96]
10% O2;
5–20 ED Sprague Dawley rats
Decreased dopamine content in the
carotid bodies; until 3 weeks after birth:
hyperventilation and
disturbed metabolism
[31]
10% O2;
5–20 ED Sprague Dawley rats
Evaluated resting ventilation and
ventilatory response; periphery: reduced
tyrosine hydroxylase activity within the
first postnatal week and enhanced later;
central areas: upregulated tyrosine
hydroxylase activity within the first
postnatal week and downregulated later
[27]
ED, embryonic day; O
2
, oxygen; PaO
2
, partial pressure of O
2
; PaCO
2
, partial pressure of carbon dioxide; A
1
R,
adenosine 1 receptor; HSP70, heat shock protein 70; ROS, reactive oxygen species; RAAS, renin-angiotensin-
aldosterone system; NO, nitric oxide; HIF, hypoxia-inducible factor; eNOS, endothelial NO synthase; p-eNOS,
phospho-eNOS; iNOS, inducible NO synthase; LF/HF, the ratio of low frequency to high frequency; HRV, heart
rate variability; ET-1, endothelin-1; AT
1
, angiotensin II type 1 receptor; SOD, superoxide dismutase; NADPH,
nicotinamide adenine dinucleotide phosphate oxidase; Ang II, angiotensin II.
Effects of prenatal hypoxia have been studied in different animal models, including
chicken (hatching 21 days), mice (full-term 21 days), rats (full-term 22 days), guinea pigs
(full-term 65 days) and sheep (full-term 147 days) [
71
,
97
] and each one has its advantages.
Sheep have a relatively similar heart size compared with humans, allowing better observa-
tion of the changes in foetal cardiovascular parameters in utero. In contrast, mice and rats
have smaller hearts than humans; however, they have a rapid reproduction rate, allowing
a relatively fast observation of changes in the postnatal period. In addition, the use of mice
in a prenatal hypoxia study allows the creation of knockouts to study selected regulatory
mechanisms. The chicken embryo develops without direct humoral contacts with the
mother, and the development can be easily manipulated [
98
]. Mice and rats are altricial
species, and their development (e.g., nephrogenesis) continues after birth [
99
], whereas
in precocial humans, sheep and guinea pigs, the development is terminated during the
prenatal period [
100
]. The difference among animal models is also related to the time of
organogenesis and the critical period of development, which can partially explain some
interspecies variation in the foetal responses to prenatal hypoxia.
Int. J. Mol. Sci. 2022,23, 2885 9 of 30
3.1.1. Reflex Response
An important regulatory mechanism responding to changes in the partial pressure
of respiratory gases (oxygen and carbon dioxide) are peripheral chemoreceptors (Table 2).
Acute prenatal hypoxia activates the carotid bodies and triggers a chemoreflex response [
70
].
Peripheral chemoreceptors activate afferent pathways to the brainstem, where they affect
the cardiovascular centres. The efferent signal from these centres is transmitted through
cholinergic stimulation of the heart and through
α
-adrenergic stimulation of blood vessels.
The result is a decrease in heart rate and an increase in peripheral vasoconstriction in acute
response; however, after prolonged prenatal hypoxia, tachycardia, and blood pressure
decrease [
70
,
71
,
95
,
96
]. The heart rate response to prenatal hypoxia is abolished after
bilateral carotid denervation, whereas the treatment does not affect the blood pressure
response [96].
Peripheral vasoconstriction due to
α
-adrenergic stimulation increases the right ven-
tricular afterload and increases the blood flow through the foramen ovale. Then, blood
from the right atrium enters the left atrium and the left ventricle, which increases blood
flow to the ascending aorta and cerebral and coronary circulation [
68
]. These effects on
the sympathetic nervous system and chemoreflex are mediated by the HIF-1
α
/HIF-2
α
ratio. Isolated carotid bodies from Hif-1
α+/−
knockout mice did not respond to short-term
hypoxia, while long-term hypoxia (repeated acute hypoxia for three days) diminished ven-
tilatory response and impaired the sensitivity to hypoxia in Hif-1
α+/−
knockout mice [
101
].
On the other hand, in the carotid bodies of Hif-2
α+/−
mice, an elevated response (breathing
abnormalities and elevated plasma noradrenaline levels) to acute hypoxia was observed. It
seems that HIF-2 has an antagonistic role to HIF-1 in oxygen sensing by carotid bodies [
102
].
Complete deficiency of HIF-1
α
or HIF-2
α
is often lethal with multiple organ (including
heart and vessels) malformations [103,104].
Hypoxia also directly affects chromaffin cells in the adrenal medulla, the primary
source of catecholamines in the foetus. The higher heart rate after prolonged hypoxia
can result from the increased catecholamine secretion [
49
,
73
]. In the foetus, the adrenal
glands are the primary source of catecholamines. The adrenal medulla in the foetus is
not innervated by the cholinergic splanchnic nerve; however, non-neuronal regulation
is directly sensitive to hypoxia [
73
]. The chemosensory function of chromaffin cells in
sheep includes the inhibition of potassium channels, membrane depolarization, increases
in intracellular calcium concentration [
73
], leading to the release of catecholamines into
plasma with an increased level persisting to postnatal life, while enzyme expression is also
affected [25,26].
In prenatal life, L-, N-, and P/Q-type Ca
2+
channels have a similar ratio in the in-
flux of Ca
2+
[
73
]. The function of K
+
is age-dependent; during the initial stages of in
utero development, chromaffin cells express more ATP-sensitive K
+
currents, while in
the late stages, more Ca
2+
activated K
+
currents are expressed [
105
]. Chromaffin cells
lose their “chemosensitivity” ability after splanchnic innervation of the adrenal medulla.
Loss of chemosensitivity is also associated with altered expression of the T- type Ca
2+
channels [106].
Regulation of the respiratory response through the nervous system appears to be
less important, as the foetus does not have its respiratory system fully developed until
birth. Therefore, the response mediated by central chemoreceptors is different in foetuses
and adults. While the foetus responds to acute hypoxia by inhibition of breathing, in
adults, acute hypoxia causes initial hyperventilation and subsequent respiratory depres-
sion
[27,31]
. Prenatal hypoxia can change the maturation of these chemoreceptors, which
can be manifested later in adulthood. In rats exposed to prenatal chronic hypoxia (10% O
2
)
from embryonic day (ED) 5 to ED 20, a change in respiratory response to acute postnatal
hypoxia (10% O
2
; 10 min) was observed as the absence of the increased respiratory rate
that is typical for the first phase of the response to hypoxia [27,31].
Int. J. Mol. Sci. 2022,23, 2885 10 of 30
3.1.2. Adenosine
Reduced oxygen availability decreases oxidative phosphorylation in the mitochondria
and stimulates the conversion of adenosine monophosphate to adenosine, the biological
effect of which is mediated via four classes of receptors: A
1
, A
2A
, A
2B
, and A
3
. Activation
of these receptors depends on adenosine concentration. A slight increase in the adenosine
level activates the A
1
receptor, which has the highest sensitivity. In contrast, activation
of the A
3
receptor occurs when adenosine concentration is exceptionally high in severe
pathologic conditions [
107
]. Adenosine indicates oxygenation in the tissues and in the case
of hypoxia, the adenosine level increases. Adenosine has a suppressive effect on plasma
cortisol levels and the function of the adrenal cortex in foetal sheep. Therefore, adenosine
can play an important role in protecting the foetus against intrauterine stress [
108
,
109
].
Adenosine also has a vasodilating effect on the coronary circulation in the sheep foetus,
increasing blood flow and ensuring oxygen supply [
110
]. In the foetus, adenosine regulation
of the heart rate is dominant compared with adrenergic and cholinergic stimulation [
107
].
In the foetus, exogenously elevated adenosine is followed by a decrease in heart rate to
asystole, while no response is observed after the administration of drugs, which increases
endogenous catecholamines or acetylcholine release [
107
]. The same effects are observed in
hypoxia, where an increased adenosine concentration activates the A
1
receptor and lowers
the heart rate [107].
Adenosine A
1
receptors are already expressed during the embryonic and organo-
genesis periods in the heart and brain [
107
], but they are not essential for normal foetal
development in normal pregnancy. Mice deficient for A
1
receptors showed no developmen-
tal defects, growth restriction, or changes in blood pressure and heart rate [
82
]; however,
adenosine A
1
receptors are important in protecting the foetus from hypoxia. Mice lacking
the A
1
receptor have more serious consequences after exposure to prenatal hypoxia, more
pronounced growth restriction, and more significant morphological changes in the heart
(disproportionate reduction in heart size, thinner ventricular walls) compared with A
1+/+
receptor and A
1+/−
receptor mice. In A
1−/−
receptor mice, decreased stabilisation in
HIF-1
α
was also observed. The reduced stabilisation in HIF-1
α
in A
1−/−
receptor mice,
resulted in the expression of genes that protect against hypoxia (adrenomedullin, carbonic
anhydrase 1, and catalase) also being reduced. In contrast, in A
1+/+
receptor and A
1+/−
receptor mice, the expression of HIF-induced genes was up-regulated [
83
,
111
]. This points
to an important link between the adenosine and HIF signalling pathways in the hypoxia in
the prenatal period (Table 2).
The importance of adenosine and its receptors in prenatal programming was reported
in a study with non-selective adenosine antagonists. In sheep treated with an adenosine
receptor antagonist, a bradycardia response, increased blood pressure, and peripheral
vasoconstriction were not observed after acute hypoxia [
77
,
95
]. Thus, adenosine receptors
appear to play a significant role in mediating the chemoreflex function [
95
]. Denervation of
peripheral chemoreceptors together with increased levels in adenosine did not reduce the
heart rate during hypoxia. In this line, blockade of the adenosine receptor and functional
chemoreflex also did not decrease the heart rate [
77
]. Except for the peripheral chemoreflex
sensitivity, adenosine mediates multilevel responses. For example, adenosine receptors
(A
2A
) in the brain are responsible for inhibiting breathing [
84
], whereas adenosine recep-
tors in the chromaffin cells of the adrenal medulla increase catecholamine levels due to
acute hypoxia.
3.1.3. Nitric Oxide, A Reactive Oxygen Species
Acute foetal hypoxia causes the dilation of blood vessels providing blood flow to
vital organs, such as the heart and brain [
59
]. Vascular dilatation is caused by increased
NO, adenosine, and prostanoids. In peripheral vessels, increased NO synthesis by en-
dothelial NO synthase (eNOS) compensates for the vasoconstrictor responses of hypoxia
(Table 2) through the actions of the chemoreflex and catecholamines [
70
]. The release of
Int. J. Mol. Sci. 2022,23, 2885 11 of 30
catecholamines is reduced by NO donors, and the inhibition of NO synthesis conversely
increases the release of catecholamines from the adrenal medulla [70].
The consequences of hypoxia on the expression of eNOS are contradictory. Some
studies show increased eNOS in the carotid artery and decreased in the femoral artery [
57
]
at the protein and gene expression levels [
59
]. In the heart, eNOS expression was increased
at the protein and decreased at the gene expression level [
85
]. The effect of hypoxia on
eNOS expression depends on the duration of hypoxia because increased ROS production
may interfere with the bioavailability of NO during prolonged hypoxia [
58
]. The dynamic
relationship between ROS and NO determines vascular tone because the hypoxia-induced
increase in ROS, and thus the foetal ROS/NO ratio, potentiates peripheral vasoconstriction
and redistribution of blood flow from the peripheral circulation to the vital organs, such
as the brain and heart [
112
]. Nicotinamide adenine dinucleotide phosphate (NADPH)
oxidase-derived ROS can react with NO to form a stable peroxynitrite anion, reducing the
bioavailability of NO. Exposure to prenatal hypoxia increases the expression of NADPH
homologue 1, which stimulates the production of superoxide and impairs endothelium-
dependent vasodilatation [
113
]. The importance of oxidative stress in prenatally pro-
grammed hypertension is demonstrated by studies in which antioxidants, such as vitamin
C and melatonin, have been administered [
2
,
42
,
86
]. Vitamin C decreased nitrotyrosine
and HSP 70 in the aorta [
2
], increased the bioavailability of NO, as well as decreased HSP
70 and increased HSP 90 in the placenta [
42
]. Vitamin C also reduced sympathetic to
parasympathetic power, thereby weakening peripheral vasoconstriction, and affecting the
brain-sparing effect [
53
,
86
]. Melatonin is a pleiotropic compound, because in addition
to its role in circadian regulation, it has strong antioxidant effects. Melatonin reduces
the mean arterial blood pressure [
87
], improves baroreflex control [
114
], and, in general,
can improve cardiac function as myocardial relaxation, myocardial contractility, and left
developed ventricular pressure [
88
]. As a result of its ability to reduce oxidative stress,
melatonin improved endothelial function, thereby exhibiting its vasodilatory effects [
88
,
89
].
In addition, melatonin also modulates activity of the autonomic nervous system, reduces
adrenergic activation, and increases cholinergic stimulation, thereby reducing blood pres-
sure [
87
,
114
]. The protective effects of melatonin, vitamin C, and other antioxidants support
the hypothesis that oxidative stress plays an important role in mediating the effects of
prenatal hypoxia on the foetus, and those antioxidants can reduce the stress consequences
on the cardiovascular system in adulthood.
Decreased oxygen concentration leads within a few minutes to the suppression of
anabolism, stimulation of anaerobic glycolysis, and inhibition of aerobic metabolism in
mitochondria [
109
]. The importance of phenotypic reprogramming of mitochondria in
the heart after an insult is known in adults and can also be important for the prenatal
programming of heart disease in adulthood (Table 2) [
90
]. The significance of mitochondria
function in cardiovascular programming is demonstrated by using MitoQ in the treatment
of prenatal hypoxia [
53
,
91
,
92
]. Administration of MitoQ, which acts downstream from
superoxide production, prevents the harmful lipid peroxidation and mitochondrial damage
initiated by superoxide. Studies point to the importance of mitochondria in cardiovascular
disease programming, maintaining the brain-sparing effect and decreasing the risk of
cardiovascular disease. Changes in mitochondrial activity depend on the duration of
prenatal hypoxia. Acute prenatal hypoxia, induced at ED 18 for 2 h in mice, decreased
the basal oxygen consumption and oxidative phosphorylation in the mitochondria of
neonates. After acute prenatal hypoxia in guinea pigs, cardiac level of ATP at the end of
hypoxia were significantly reduced, but no changes in cardiac metabolism were observed
in neonates [
93
]. Chronic prenatal hypoxia, from ED 14 until delivery, increases the basal
oxygen consumption and oxidative phosphorylation in the central nervous system of
neonates. Chronic prenatal hypoxia increases the expression of Nfe2l2 (Nuclear factor
erythroid-derived 2-like 2), which is responsible for protection against oxidative stress and
mitochondrial oxidative stress, with no effect on antioxidant enzyme expression in the foetal
heart. In contrast, in the adult offspring rats, an increased expression of Nfe2l2, catalase and
Int. J. Mol. Sci. 2022,23, 2885 12 of 30
glutathione peroxidase was observed in the heart as a compensatory antioxidant response
to prenatal hypoxia [
92
]. These results indicate that chronic prenatal hypoxia leads to the
adaptation of the mitochondrial function in a duration-dependent manner [47].
3.1.4. Renin-Angiotensin-Aldosterone System
The renin-angiotensin-aldosterone system is important in regulating blood pressure,
electrolytes, and water homeostasis. Decreased renal blood flow induces the release of renin
from juxtaglomerular cells and the conversion of inactive angiotensinogen to angiotensin I,
which is converted to Ang II by the angiotensin-converting enzyme. The biological effects
of Ang II are mediated through AT
1
and AT
2
receptors and the RAAS functions differ
between adults and the developing foetus [
115
]. In the adults, the RAAS is important
for long-term regulation of blood pressure and its effects are mediated by AT
1
receptors
via peripheral vasoconstriction, fluid balance, and electrolyte control, whereas the AT
2
receptor is responsible for a counterregulatory role through stimulation vasodilatation,
natriuresis and inhibition proliferation and cell differentiation [
116
]. During the prenatal
period, both AT
1
and AT
2
receptors are present and are involved in the control of neural
differentiation, cell apoptosis and cell proliferation [
115
]. Exposure to prenatal hypoxia
results in cardiac fibrosis and hypertrophy due to an adaptive response [
117
] and activation
of the signalling pathways related to the AT
1
receptor and the transforming growth factor-
β
1. Angiotensin II stimulates the synthesis of collagen and extracellular matrix proteins
through activation of the AT
1
receptor and transforming the growth factor-
β
1 [
117
]. The
development of fibrosis and cardiac hypertrophy in foetuses exposed to prenatal hypoxia
can be amplified by increased salt intake, which only supports the role of RAAS in the
development of these morphological changes [94]. Moreover, AT1and AT2receptors play
a significant role in the prenatal programming of blood pressure and setting the set points
of its regulatory mechanisms (Table 2) [
33
,
94
]. This conclusion is supported by using
RAAS blockers, which reduce blood pressure and eliminate the effects caused by prenatal
hypoxia in the cardiovascular system [
118
]. Angiotensin II receptors are important for
the development of nephrons and the kidneys, can increase sympathetic nervous activity,
oxidative stress, and cause cardiac and renal fibrosis associated with the development of
hypertension and other cardiovascular diseases.
Hypoxia-induced HIF-1
α
stimulates the expression of AT
1
receptors and the angiotensin-
converting enzyme [
55
], while silencing of HIF-1
α
suppressed Ang II-mediated effects
in the kidney [
56
]. In foetal thoracic aortas of rats (ED 21), losartan, the AT
1
receptor
antagonist, suppressed Ang II-mediated vessel contractions induced by hypoxia via the
NADPH oxidase 4-dependent pathways [
33
], whereas the effect of hypoxia was more pro-
nounced in rats when offspring were exposed prenatally to a high salt diet [
94
], suggesting
the participation of structural changes in the kidney. The experiments indicate a strong
interaction of RAAS and prenatal hypoxia in the development of hypertension [78].
Acute hypoxia in the middle of pregnancy causes short-term changes in the kidneys of
sheep. These short-term compensatory mechanisms, such as glomerular hypertrophy, allow
renal function to be maintained, but nephron deficiency later in life may lead to an inability
to maintain fluid homeostasis and increase the susceptibility to hypertension and renal
disease. Decreased nephron formation may be due to impaired morphogenesis, increased
apoptosis, and changes in RAAS activity. The critical period of nephron formation depends
on the animal model and is found in the interval from the first trimester to the early postna-
tal stage [
119
]. Decreased nephron formation may also be due to growth factors, because
in vitro
studies showed that transforming growth factor-
β
1 reduced the nephron num-
ber [
120
], inhibited ureteric branching and affected tubular development [
121
]. Increased
expression in transforming growth factor-
β
1 was also observed in other “a poor in utero
environment” models and was associated with a reduced number of nephrons
[119,122]
.
Repeated exposure to intermittent hypoxia for two weeks in sheep did not lead to a change
in body or organ weight, except for the kidneys, which were smaller in sheep exposed to
hypoxia, and the reduction in kidney weight may be due to decreased renal blood flow
Int. J. Mol. Sci. 2022,23, 2885 13 of 30
and growth factors [
48
]. A decreased nephron number and reduced weight of the kidneys
are often associated with intrauterine growth restriction; however, fewer nephrons have
also been observed in children with a “normal” birth weight. This may be of clinical signifi-
cance because a decreased nephron number and “normal” birth weight are associated with
sudden infant death syndrome [48,123].
3.1.5. Morphological-Functional Changes in the Heart and Blood Vessels
Prenatal hypoxia causes peripheral vasoconstriction and bradycardia. As a result,
pressure and volume overload of the heart occurs and leads to heart remodelling. The
impairment of prenatal development can induce changes in the development of the heart
conduction system, which is associated with sudden infant death syndrome. Disorders at
the level of the conduction system can reflect deregulated atrial, atrioventricular node, or
conduction pathways and mutations in sodium channels [
124
,
125
]. If prenatal hypoxia is
prolonged, the heart becomes hypertrophied to maintain its function [
126
]. As a result of
short-term hypoxia in the last trimester of pregnancy, an increase in mononuclear cardiomy-
ocytes was observed in both the right and left ventricles and was accompanied by increased
collagen deposition [
52
]. Moreover, the elevated length to width ratio of cardiomyocytes
was found in the right ventricle [
52
] and similar results in heart development were observed
after chronic prenatal hypoxia [
127
]. Development of the cardiomyocytes is regulated by
Ang II, cortisol, and insulin-like growth factor I and II [
110
,
128
]. Prenatal hypoxia can
affect the development of cardiomyocytes through these factors and has an important
role in oxidative stress [
52
]. The observed changes can cause cardiac dysfunction under
pathological conditions and ischaemia-reperfusion injury [34].
Prenatal hypoxia between ED 11.5–13.5 causes the most significant changes in the
heart, compared with the brain and spinal cord of mice foetuses. As a result of the decreased
cardiomyocyte proliferation, the ventricular myocardium was thin, the epicardium was
detached, and the ventricular mass and wall thickness was reduced. For example, sheep
foetuses affected by prenatal hypoxia had smaller myocytes than the controls [
129
]. In
general, prenatal hypoxia slows heart maturation [
130
] and these morphological changes
accompany reduced cardiac output and diastolic function [129].
Exposure to chronic hypoxia (10
±
1% O
2
) from ED 7 to ED 21 in rats increased the
relative weight of the heart and brain [
38
]. Another study with chronic hypoxia (13% O
2
)
from ED 6 to ED 20 in rats did not show a change in heart weight or morphological changes
in the ventricles; however, isolated offspring hearts had increased ventricular contractility
(dP/dt
max
), as well as a suppressed chronotropic response to a muscarinic agonist and
an increased response to a
β1
-adrenoreceptor agonist due to chronic prenatal hypoxia [
2
].
Meanwhile, another study in sheep showed that prenatal hypoxia from ED 103 (full-term
147 days) increased the left ventricular end-diastolic pressure and decreased myocardial
contractility and relaxation in the isolated heart [
131
]. Moreover, a study associated with
intrauterine growth restriction induced by intermittent hypoxia from ED 14 to ED 18
showed no changes in dP/dt
max
on ED 22 and postnatally; however, these rats had an
increased inotropic response [
50
]. On the other hand, in rats exposed to 12 h of hypoxia on
ED 20, no differences in heart rate and blood pressure response to noradrenaline compared
with the control rats were observed [
132
], thus, it seems that changes are prenatal hypoxia
duration dependent.
Prenatal hypoxia also increases the aortic wall thickness [
2
,
28
]. In 16-month-old rats,
prenatal hypoxia impaired the endothelial function, thickening and deposition of fibrils
in the intima, and the migration and proliferation of vascular smooth muscle cells to the
intima [
38
]. Morphological changes of the heart and blood vessels can be associated with
an increased load on the heart and blood vessels and are likely to be mediated by oxidative
stress and endothelial dysfunction [
2
,
75
,
131
]. Treatment with vitamin C [
2
], the NADPH
inhibitor apocynin, and superoxide dismutase [
9
] eliminated the adverse effects of prenatal
hypoxia on endothelial dysfunction and morphological changes of the cardiovascular
system; however, administration of MitoQ improved the endothelial function in rats
Int. J. Mol. Sci. 2022,23, 2885 14 of 30
exposed to prenatal hypoxia but did not normalise hyperactivity of the sympathetic nervous
system [
14
,
133
]. These findings point to the complexity of the mechanisms involved in the
prenatal programming of the cardiovascular system.
3.2. Placenta
Maternal and foetal blood do not mix, but their circulations are in close proximity in
a newly formed fetomaternal interface, the placenta. This transient organ provides the
environment for the exchange of nutrients and gases between the mother and the foetus
and protects the foetus from deleterious environmental factors [
134
]. Oxygen crosses the
placental barrier by simple diffusion down its concentration gradient, so the efficiency of
its transport depends mostly on uterine blood flow, placental morphology, and placental
metabolism [
135
]. During pregnancy, uteroplacental blood flow increases several times
to meet foetal demands and, therefore, structural changes must constantly occur in the
placenta [
136
,
137
]. If the placenta is exposed to adverse effects, such as hypoxia, its
structure and function must change, thus sparing the developing foetus from oxygen
deprivation [
138
]. On the other hand, when placental development is disturbed, the
placental oxygen supply might become limited [43,139].
Placental function is linked to its structure. In humans, maternal spiral arteries
deliver oxygenated blood into the space between placental chorionic villi, so the villous
brush border membrane is washed directly by maternal blood. On the foetal side of
the placenta, chorionic villi encompass foetal capillary networks. Maternal blood is thus
separated from foetal circulation by several tissue layers [
140
]. Although some mammals
have different numbers of barrier layers, the placental diffusing capacity remains similar
among these species [
141
]. During the first trimester of human pregnancy, maternal spiral
arteries are clogged with trophoblast cells derived from the developing embryo, resulting
in fetoplacental hypoxia. At this stage, hypoxia is not pathological, on the contrary, it
drives the placental and initial foetal development [
142
]. Meanwhile, clogged maternal
arteries undergo physiological remodelling. This is a crucial process to ensure adequate
placental perfusion throughout pregnancy, since foetal oxygenation depends strongly
on uteroplacental blood flow. During physiological vascular conversion, the endothelial
lining and vascular smooth muscle layer are replaced by fibrinoid, leading to vascular
lumen enlargement. Remodelled vessels cannot respond to vasoactive substances to the
degree they did before the remodelling [
143
], meaning that maternal blood flows into the
intervillous space more continuously and under lower pressure [
144
]. Such low-resistance
flow protects the chorionic villi and provides adequate time for the exchange of nutrients
and gases. Moreover, the pressure difference between the intervillous space and foetal
capillaries affects the thickness of the villous membrane, thus influencing the placental
diffusing capacity [144].
Abnormal placental development with poor spiral artery remodelling can adversely
affect placental haemodynamics and placental diffusing capacity [
139
,
145
] and lower
foetal oxygenation may result from abnormal villous development [
146
]. Together, the
inadequate conversion of spiral arteries along with abnormal villous development can
cause placental insufficiency and jeopardize foetal development [
145
]. The shallow, or
even absent, trophoblast invasion of spiral arteries is considered one of the causes of
preeclampsia [
147
]. In preeclampsia, insufficiently remodelled spiral arteries still have
a muscle layer [
148
,
149
], so they are more reactive to vasoactive substances [
80
]. In addition,
insufficient remodelling can be accompanied by placental atherosis, which is characterized
by fibrinoid necrosis of the vessel wall [
150
] and thrombosis [
151
], both contributing to
uteroplacental ischaemia-reperfusion injury and subsequent oxidative stress [
139
]. As
a result, intermittent placental perfusion is more frequent throughout the pregnancy than
is normal [
139
]. The intermittent perfusion becomes a problem, especially towards the end
of a pregnancy, when fetoplacental oxygen consumption is at its peak [148].
Placental vessels lack innervation, and their reactivity mostly results from locally
produced substances [
80
]. Typically, if shear stress is high, placental endothelial cells
Int. J. Mol. Sci. 2022,23, 2885 15 of 30
produce NO, so placental vascular resistance decreases; however, in placental vessels from
growth-restricted foetuses, the shear stress-induced vasodilation is impaired, resulting
in a parallel increase in placental vascular resistance [
136
]. The strongest vasoconstrictor
produced by preeclamptic placental tissue is probably thromboxane, but other local sub-
stances are involved, such as Ang II and endothelin. Placental vasoreactivity is amplified by
decreased prostacyclin and prostaglandin E2 production [
80
]. Finally, the chronic increase
in adenosine concentrations in preeclampsia stimulates the production of anti-angiogenic
soluble fms-like tyrosine kinase-1, a non-membrane associated splice variant of receptor 1
for vascular endothelial growth factor (VEGF). It binds the angiogenic VEGF, decreasing its
free circulating concentrations and reducing vessel growth and placental vasculature [
152
].
An inappropriate oxygen environment can induce changes in the placental structure,
which might be beneficial for improving foetal oxygenation. A placental barrier can become
thinner, capillary diameter increases and uteroplacental vascular resistance decreases, so
a more efficient diffusion is achieved [
138
]. These changes are mediated by HIF-1
α
target
genes and their proteins, such as VEGF and erythropoietin [
153
]. Moreover, hypoxia can
stimulate the expression of arginase-2, an enzyme responsible for decreased NO produc-
tion [
136
]. Higgins et al. demonstrated in a murine model that there is an oxygen threshold
below which the placenta cannot compensate for the lack of oxygen and intrauterine growth
restriction occurs. Their experiment showed that an inhalation of 13% O
2
during pregnancy
led to structural changes in the placenta (reduction of the thickness of the interhaemal
membrane, increased labyrinth zone volume, reduced trophoblast volume, increased pla-
cental capacity for transport of nutrients and O
2
to the foetus), which spared foetal growth.
On the other hand, when pregnant dams inhaled 10% O
2
, the placental barrier became
thicker and the exchange surface area was reduced, so the placental diffusing capacity was
negatively affected, and foetal growth restriction occurred.
Along with structural changes, placental metabolism is also modified by hypoxia.
The hypoxic placenta consumes less oxygen but increases glucose transport and uptake
for anaerobic glycolysis. The placenta is susceptible to oxidative stress due to its high
metabolic activity; however, with increasing foetal oxygen requirements and increased
metabolic activity, the antioxidant capacity of the placenta gradually increases [
154
]. Such
reprogramming can protect the foetus from growth restriction [
155
], but if the transplacental
glucose transport is decreased and placental consumption is still increased, the foetus
becomes hypoglycaemic, resulting in growth restriction [
153
,
156
]. Two other factors can
affect placental metabolism: the stage of pregnancy when hypoxia occurs and maternal
food intake [
155
]. Hypoxia can modulate maternal food intake, therefore, it might be
difficult sometimes to distinguish whether the effects are due to a lack of oxygen or a lack
of nutrients. The same applies for glucocorticoids; hypoxia can also induce glucocorticoid
secretion [
157
]. A foetus is protected from maternal glucocorticoids by the placental enzyme
11
β
-hydroxysteroid dehydrogenase (11
β
-HSD) type 2, converting the biologically active
cortisol to the inactive cortisone. Hypoxia reduces the expression of 11
β
-HSD type 2 [
81
]
and thus allows more glucocorticoids to cross the placental barrier. In contrast, hypoxia
does not affect the expression of 11
β
-HSD type 1, which converts inactive cortisone to active
cortisol [
158
]. Many articles have analysed the effect of antenatal glucocorticoid exposure
on the development of the foetal cardiovascular system [
159
]. Antenatal glucocorticoids
have direct and mediated (Ang II, catecholamines) pressor and morphological effects, such
as cardiomyocytes maturation as well as growth and differentiation of the smooth muscle
and endothelial cells in vessels [
160
]. Based on these findings, the placenta integrates
multiple signals to compensate for the foetal demands. Whether these adaptations are
beneficial for the foetus depends not only on the severity of hypoxia but also on other
factors that may buffer or amplify the effects of hypoxia.
3.3. Mother
The foetus is entirely dependent on maternal oxygen supply and therefore, maternal
hypoxaemia strongly affects the foetus. Maternal hypoxaemia can arise from different aeti-
Int. J. Mol. Sci. 2022,23, 2885 16 of 30
ologies, which are related to maternal health conditions, such as maternal haematological
disorders, chronic pulmonary disease, and heart disease, or various environmental factors.
Hypoxia is usually studied by inhaling low oxygen air, which mimics the environment
at high altitudes. Millions of people live permanently in high-altitude environments and
are expected to be genetically well adapted. Indeed, women living in high altitudes have
a more significant increase in uterine perfusion during gestation and because of that, better
foetal outcomes [
161
]. Maternal health conditions can result in an insufficient oxygen
supply, even when the mother herself is not hypoxic. In such cases, foetal hypoxia could be
a consequence of reduced uteroplacental perfusion or increased fetoplacental metabolism.
Gestational diabetes is one of the most common complications of pregnancy. Accord-
ing to the studied population, its prevalence ranges from 1.7% to 11.6% [
162
]. During
pregnancy, the maternal metabolism changes to ensure optimal foetal development, and
a pregnant woman becomes insulin resistant to provide the foetus with a sufficient amount
of glucose. When the pancreas of a hyperglycaemic pregnant woman cannot produce
enough insulin to maintain glycaemia [
163
], more glucose passes through the placental bar-
rier to the foetus, which becomes hyperglycaemic. Consequently, foetal hyperinsulinaemia
develops with a consequent increase in size and metabolism of the foetus [
164
]. These
changes are reflected in increased uteroplacental and foetal oxygen consumption [
165
],
and if fetoplacental demands exceed the maternal oxygen supply, hypoxia occurs [
166
].
Moreover, gestational diabetes is associated with a changing “zigzag” pattern of heart rate
variability in the foetus [
167
]. Similar changes were observed during the second stage
of parturition when an overstretched or compressed umbilical cord occurred, or during
reduced oxygen availability because of uterine contractions [
167
]. The observed changes
suggest that heart rate variability and the “zigzag” profile may be used as an early marker
of prenatal hypoxia and not only in pregnancies with gestational diabetes [167].
Haematological disorders. Epidemiological data show that every fifth pregnant
woman is anaemic and in developing countries, the prevalence might even reach 75% [
168
].
During the first trimester, a woman’s blood volume starts to expand, followed by a later
increase in red blood cell mass. These pregnancy-induced changes result in physiological
anaemia [
169
]. Since iron is needed for red blood cell formation, its deficiency reduces the
capacity of blood to carry oxygen [
170
]. Interestingly, compensatory changes may lead
to paradoxically higher oxygen content in the umbilical cord [
171
]. Another example of
haematological disorders may be an abnormal, rigid sickle shape of erythrocytes, observed
in thalassemia [64].
Pulmonary complications. Pregnancy-induced changes may also contribute to the
development of obstructive sleep apnoea, whose prevalence reaches up to 26% in late
pregnancy because of a higher maternal body mass index [
172
]. Obstructive sleep apnoea is
characterized by episodes of hypopnoea or even apnoea resulting in maternal intermittent
hypoxaemia and hypercapnia [
173
]. Even though such a shortage of oxygen is not necessar-
ily transmitted to the foetus [
174
], data indicate the association between obstructive sleep
apnoea and adverse foetal growth [
175
]. Among other respiratory disorders, asthma is the
most common during pregnancy, with a worldwide prevalence of 2–13% [
176
]. When air-
ways are obstructed, ventilation becomes uneven, and maternal arterial oxygen saturation
decreases [
177
]. Acute respiratory diseases such as bronchitis, and pneumonia can lead to
maternal respiratory failure, represent a risk for the foetus, and are a common pulmonary
problem during pregnancy [64].
Cardiac diseases occur in 1% of pregnant women [
178
]. Maternal cardiac output
increases throughout a normal pregnancy until reaches more than 30% of the non-pregnant
value [
179
]. This physiological change, accompanied by a decrease in systemic resistance,
is necessary to ensure adequate foetal oxygenation. If a pregnant woman suffers from heart
disease, the heart may not adapt to this increased load [
180
] leading to arrhythmias, heart
failure [
181
], and pulmonary oedema. In such cases, insufficient gas exchange in maternal
lungs causes hypoxaemia also in the foetus [180].
Int. J. Mol. Sci. 2022,23, 2885 17 of 30
Lifestyle. Maternal hypoxia can also develop due to bad lifestyle habits, such as
a high-fat diet, smoking, or alcohol consumption. Consumption of a high-fat diet is
associated with lower uteroplacental perfusion. Moreover, if a high-fat diet is accompanied
by maternal hyperinsulinaemia, it can result in placental dysfunction [
182
] and the placental
oxygen transport it might become limited. Moreover, obese women are more susceptible to
developing the above-mentioned diseases, such as gestational diabetes or obstructive sleep
apnoea [
183
], which may further increase the risk of hypoxia. Active smoking causes a rapid
increase in maternal pulse and blood pressure. These cardiovascular changes result from
the action of serum catecholamines, whose concentration increases within a few minutes
after smoking [
184
]. When the uterine vessels are constricted, uteroplacental blood flow
might become temporarily limited, while maternal concentrations of carboxyhaemoglobin
also increase, resulting in a lower oxygen supply for the foetus, thus making hypoxia
even more pronounced [
184
]. A recent study showed that passive smoking might also
cause foetal hypoxia [
185
]. Alcohol consumption results in placental oxidative stress and
a subsequent decrease in NO availability [
186
]. Even drinking coffee during pregnancy
could potentially affect foetal oxygenation by stimulating the maternal and placental
renin-angiotensin system [187] and maternal catecholamine secretion [188].
4. Factors Affecting the Consequences of Hypoxia
In general, the effects of prenatal hypoxia depend on several variables, such as the
duration of prenatal hypoxia, environmental factors, sex of the foetus, stage of development,
and phase of the day when hypoxia occurs.
4.1. Sex
Animal studies suggest a sex-dependent susceptibility to cardiovascular disease in
adulthood after exposure to prenatal insults. Female offspring possess protective mech-
anisms against prenatal hypoxia programming effects, while male offspring have an in-
creased susceptibility to cardiovascular diseases [
189
] and the negative consequences of
prenatal hypoxia are manifested differently at the local and systemic levels depending
on sex.
Another sex-dependent effect of prenatal hypoxia is the vasoactive response of vessels
to endothelin-1. The mesenteric arteries of male rats exposed to prenatal hypoxia show an
increased vasoconstrictive response to endothelin-1 as compared with that of female rats.
The administration of an endothelin-1 antagonist results in a significantly greater blood
pressure reduction in males as compared with that in females [
39
]. Sex-dependent changes
were also observed in the ryanodine receptor 2 in the heart because prenatal hypoxia
increased the ryanodine receptor 2 in males, but not in females [
190
]. Moreover, males have
a higher susceptibility to the development of hypertension at an earlier age [
9
,
94
] and have
an increased susceptibility to ischaemia/reperfusion injury in comparison with females [
16
].
This difference can be explained by decreased protein kinase C
ε
activity through an epi-
genetic modification [
10
], because this enzyme is important in cardioprotection against
ischaemia/reperfusion injury [191].
The kidney of the male foetus is more sensitive to hypoxia than that of the female
foetus, because no glomerular loss or renal fibrosis was observed in the hypoxic female
rat foetus. Males have more glomeruli than females under basal physiological conditions,
and prenatal hypoxia causes a reduction up to 25% compared with controls [
94
]. Renin
expression is higher in juvenile male offspring exposed to prenatal hypoxia than in females
but without differences in the AT
1
receptor and angiotensin-converting enzyme gene
expression in the kidney [
94
]. The difference in the renal response to prenatal hypoxia
between females and males suggests that mechanisms exist in females that protect the
kidney from prenatal hypoxia at an early age.
Chronic prenatal hypoxia (14% O
2
; ED 6–18) in offspring male mice (8-months-old) led
to an increased ROS production and lower respiratory capacity, which was associated with
a reduced protein expression of mitochondrial complex I, II, and IV. In females of the same
Int. J. Mol. Sci. 2022,23, 2885 18 of 30
age, the opposite effect was observed, with a higher respiratory capacity and lower ROS
production that was associated with the increased enzymatic activity of complex IV [
44
].
Prenatal hypoxia can be experimentally treated by MitoQ, which is a mitochondria-targeted
antioxidant used for the treatment of oxidative stress. MitoQ has protective effects in
the foetus of males and females, increasing placental efficiency and decreasing placental
superoxide concentration, but only an improved oxygenation and normalized hypoxia-
induced gene expression in females [
192
]. Thus, it seems that MitoQ has more protective
effects in females than in males.
Ovariectomy and castration reduce the sex differences in blood pressure due to placen-
tal insufficiency [
193
]. Placental insufficiency in rats led to intrauterine growth restriction
and increased blood pressure in 3-months-old males, while females of the same age were
normotensive [
194
]. In the case of plasma oestrogen levels, no differences were observed
between females prenatally exposed to hypoxia and controls [
195
]. Ovariectomy in females
exposed to prenatal hypoxia increased the blood pressure response to Ang II, which is
normally reduced due to prenatal hypoxia; however, oestrogen administration did not
affect the blood pressure response in hypoxic females. The role of the ovary in regulat-
ing blood pressure and cardiovascular function is probably related to oestrogen and its
downstream signalling pathways and its relationship with other hormones [195]. Despite
apparent ambiguities, the oestrogen receptors are involved in cardio-protection. Oestro-
gen receptor stimulation leads to eNOS activation, AT
1
receptor up-regulation and AT
2
receptor down-regulation, while oestrogen receptor knockouts reduce cardio-protection
and increase the susceptibility to injury from ischemia/reperfusion injury [
196
]. These
effects are age-dependent, because in older ovariectomised rats, oestrogen supplementation
decreases the AT1receptor and increases the AT2receptor expression [196].
The role of androgen in prenatal programming is less understood. In 12-months-old
females with intrauterine growth restriction, increased values of plasma testosterone and
blood pressure were observed, and blockade of the androgen receptor decreased blood
pressure [
197
]. Similar to oestrogen, testosterone interacts with the RAAS, while androgen
receptor blockers decrease the AT
1
receptor and angiotensin-converting enzyme [
198
].
Moreover, enalapril (an angiotensin-converting enzyme inhibitor) suppressed the increase
of blood pressure in a intrauterine growth restriction female, however this was less signifi-
cant if the androgen receptor was blocked. A similar effect was observed in males [
197
].
Serum testosterone and oestradiol were increased in male rats due to prenatal hypoxia [
199
]
and castration in these animals reduced blood pressure, while an administration of enalapril
caused a more pronounced decrease in blood pressure in intact males compared with cas-
trated rats [
198
]. This knowledge points to the complexity of prenatal programming and its
effect in sex-dependent manners.
4.2. Circadian Variability
The effects of prenatal hypoxia on the cardiovascular system can also be modified
by the circadian system because all important organs (kidneys, heart, and blood vessels)
are under the circadian control of the master circadian oscillator localised in the suprachi-
asmatic nuclei in the hypothalamus of the brain. Moreover, all these organs, as well as
nearly all cells in the body, contain peripheral oscillators, which are synchronised through
humoral and neural pathways [
200
]. The central and peripheral oscillators generate circa-
dian oscillations based on the rhythmic expression of so-called clock genes (Clock,Bmal1,
Cry1,Per1,Per2,Per3,Dec1,Dec2, and Rev-erba). This molecular mechanism is based on
the complex transcription–translation feedback loops, in which the transcriptional fac-
tors BMAL1 and CLOCK govern the rhythmic expression of negative factors encoded by
genes Per1,2,3 and Cry1 and 2, which feedback and inhibit the expression of the Bmal1
and Clock genes [
201
,
202
]. Heterodimer BMAL1 and CLOCK also activates the expression
of Rev-erba, which protein inhibits Bmal1. Similarly, Dec1 and Dec2 are transactivated by
heterodimer [203]. Circadian rhythms are endogenously generated and synchronised pre-
dominantly by the light–dark cycle to rhythmic environmental conditions, but other cyclic
Int. J. Mol. Sci. 2022,23, 2885 19 of 30
changes, such as feed intake, can efficiently synchronise the peripheral organs, such as the
liver [204,205]. During the gravidity, clock gene expression is significantly changed [206].
The endogenous circadian rhythms in the foetus develop gradually and start to func-
tion autonomously only after birth [
207
]. Nutrients and maternal humoral factors, such as
melatonin and glucocorticoids are important synchronizing factors for the foetus [
200
,
208
].
Maternal corticosterone levels increase significantly during gravidity and exhibit circadian
rhythms, which are lost at the end of gravidity [
206
]. Glucocorticoids can set a circa-
dian clock in the foetus and also accelerate the development of the circadian oscillator
and circadian rhythmicity [
208
]. Moreover, the placental enzyme 11
β
-HSD type 2, which
has the important mediatory function regarding the actions of glucocorticoids, is directly
regulated by clock genes. The activity of 11
β
-HSD type 2 is highest in the morning, cor-
responding to the peak of maternal glucocorticoid secretion [
209
]. Thus, such an activity
pattern protects the foetus from excessive glucocorticoid exposure [
209
]. In addition, the
expression of placental glucose and amino acid transporters may also show a circadian
pattern [
210
], suggesting that desynchronization might probably affect placental nutrient
transport. Moreover, other regulatory mechanisms maintaining the homeostasis of the
cardiovascular system, such as NO, autonomic nervous system and RAAS, exhibit distinct
circadian rhythms. In the foetus, heart rate has a significant daily rhythm, which is modified
by sex, maternal locomotor activity and season [
211
]. The rhythm is clearly imposed by
maternal factors, but their interplay with the development of the circadian system of the
foetus and other factors, which can interfere with them, can have clinical significance [
211
].
Gestational hypoxia can regulate trophoblasts’ proliferation, migration, and invasion
ability through Clock expression. The expression of Clock in the placenta was significantly
higher in a prenatal hypoxia group than in controls, and the silencing of Clock caused
an improvement of the proliferation, migration, and invasion ability of trophoblasts. Since
Clock is more stable than Hif, it was suggested as a more reliable marker of the hypoxia in
the placenta [
212
]. Moreover, recent studies indicate that manipulating the clock genes can
act as a therapeutic tool to minimize the pathologies associated with hypoxia [62].
4.2.1. Hypoxia-Inducible Factors
Circadian clocks cause daily oscillations of oxygen levels under physiological condi-
tions with increased consumption during the active phase of the day, which is associated
with physical activity and food intake, because both activities require high oxygen con-
sumption [
213
]. Likewise, organ oxygenation is rhythmic, reaching peak levels during
the active phase [
214
]. Moreover, oxygen is an important synchronizing factor for the
circadian rhythm. Many studies suggest a two-way relationship between the transcription
factors responding to hypoxia and clock genes [
215
,
216
] (Figure 2). The activity of HIF-1 is
regulated by circadian clock components and the increased expression of PER2 stabilises
and increases HIF-1 activity. In addition, hypoxia increased the expression of Dec1, which
is also enhanced by light [
203
]. The reciprocal relationship between HIFs and the circadian
clock is considered a therapeutic target and can contribute to the development of new
therapeutic approaches [217].
Stable HIF-1 binds to the hypoxia response element, which is found in the promoter or
enhancer region of hundreds of genes, thereby increasing the transcription of these target
genes above a basal level. Moreover, HIF-1
α
may be able to bind to the E-box of clock genes
and influence the transcription–translation feedback loop [
218
]. Studies suggest that the
physiological rhythms of oxygen reset the molecular clock in cultured cells [
214
]. In Hif-1
α
deficient cells, the oxygen rhythms did not induce cyclic expression of the clock genes,
and the expression levels of clock genes were consistently low compared with control
cells, except for Clock, which was increased in the Hif-1
α
deficient cells. This suggests
that HIF-1
α
represents a link between oxygen and the circadian clock [
219
]. Exposure to
intermittent hypoxia in adult mice affects clock genes’ expression more in the central (the
brain) than in the peripheral tissue (the liver). In the brain, Arntl and Nr1d1 expression
became arrhythmic compared to Cry2 expression. The expression of Per1 and Per2 resulted
Int. J. Mol. Sci. 2022,23, 2885 20 of 30
in their lower amplitude after hypoxia. In the liver, Per1 and Nr1d1 rhythms had a reduced
amplitude, while Clock became arrhythmic [
220
]. The effects of hypoxia on the circadian
clock were not analysed in the prenatal period; however, prenatal maternal stress had
long-lasting effects on the circadian system in offspring, because desynchrony among
individual SCN neurones was observed and canonical clock gene rhythms were impaired
in the central oscillator and peripheral tissues [
221
]. The results suggest that the effects
of hypoxia on canonical clock genes are tissue-specific and illustrate the way in which
hypoxia can exert its influence on health in adulthood.
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 20 of 31
Figure 2. Interaction between prenatal hypoxia and the circadian system. Prenatal hypoxia de-
creases oxygen bioavailability in the tissues of the foetus. The sensitivity of the cell to decreased
oxygen supply is mediated by hypoxia-inducible transcription factors, which interact with multiple
physiological systems, including bi-directional interaction with the circadian system. Transcription
factors induced by hypoxia show daily rhythms and directly bind to the E-box of the clock genes,
thereby modulating the function of the circadian system. Transcriptional factors that respond to
hypoxia also interact with the cardiovascular regulatory mechanisms to maintain homeostasis and
sufficient blood flow through vital organs by increased peripheral resistance and reduction of oxy-
gen consumption. ANS, autonomic nervous system; NO, nitric oxide; ROS, reactive oxygen species;
RAAS, renin-angiotensin-aldosterone system.
Stable HIF-1 binds to the hypoxia response element, which is found in the promoter
or enhancer region of hundreds of genes, thereby increasing the transcription of these tar-
get genes above a basal level. Moreover, HIF-1α may be able to bind to the E-box of clock
genes and influence the transcription–translation feedback loop [218]. Studies suggest that
the physiological rhythms of oxygen reset the molecular clock in cultured cells [214]. In
Hif-1α deficient cells, the oxygen rhythms did not induce cyclic expression of the clock
genes, and the expression levels of clock genes were consistently low compared with con-
trol cells, except for Clock, which was increased in the Hif-1α deficient cells. This suggests
that HIF-1α represents a link between oxygen and the circadian clock [219]. Exposure to
intermittent hypoxia in adult mice affects clock genes’ expression more in the central (the
brain) than in the peripheral tissue (the liver). In the brain, Arntl and Nr1d1 expression
became arrhythmic compared to Cry2 expression. The expression of Per1 and Per2 resulted
in their lower amplitude after hypoxia. In the liver, Per1 and Nr1d1 rhythms had a reduced
amplitude, while Clock became arrhythmic [220]. The effects of hypoxia on the circadian
clock were not analysed in the prenatal period; however, prenatal maternal stress had
long-lasting effects on the circadian system in offspring, because desynchrony among in-
dividual SCN neurones was observed and canonical clock gene rhythms were impaired
in the central oscillator and peripheral tissues [221]. The results suggest that the effects of
hypoxia on canonical clock genes are tissue-specific and illustrate the way in which hy-
poxia can exert its influence on health in adulthood.
On the other hand, the effects of prenatal hypoxia can be modified by circadian reg-
ulation because the clock genes regulate the transcription factors induced by hypoxia (Fig-
ure 2). The transcript of Hif-1α is constant, while the nuclear protein HIF-1α levels in the
kidneys and brain have circadian rhythms [214]. An analysis of organs, such as the liver,
kidneys, and lungs, revealed that the lowest time-dependent transcription response was
in the lungs. A similar response to hypoxia was observed in conditions without synchro-
nizing factors; therefore, it is assumed that the transcription response to hypoxia is endog-
enously regulated [213]. This response was affected in mice with disrupted circadian sys-
tems, and the time-dependent response was lost [213].
Plasticity and critical windows in prenatal development are regulated across multi-
ple scales, from milliseconds and minutes, controlled by neuronal oscillations, up to os-
cillations with a key role of the clock genes. Moreover, plasticity windows are sensitive to
Figure 2.
Interaction between prenatal hypoxia and the circadian system. Prenatal hypoxia de-
creases oxygen bioavailability in the tissues of the foetus. The sensitivity of the cell to decreased
oxygen supply is mediated by hypoxia-inducible transcription factors, which interact with multiple
physiological systems, including bi-directional interaction with the circadian system. Transcription
factors induced by hypoxia show daily rhythms and directly bind to the E-box of the clock genes,
thereby modulating the function of the circadian system. Transcriptional factors that respond to
hypoxia also interact with the cardiovascular regulatory mechanisms to maintain homeostasis and
sufficient blood flow through vital organs by increased peripheral resistance and reduction of oxygen
consumption. ANS, autonomic nervous system; NO, nitric oxide; ROS, reactive oxygen species;
RAAS, renin-angiotensin-aldosterone system.
On the other hand, the effects of prenatal hypoxia can be modified by circadian
regulation because the clock genes regulate the transcription factors induced by hypoxia
(Figure 2). The transcript of Hif-1
α
is constant, while the nuclear protein HIF-1
α
levels in
the kidneys and brain have circadian rhythms [
214
]. An analysis of organs, such as the liver,
kidneys, and lungs, revealed that the lowest time-dependent transcription response was in
the lungs. A similar response to hypoxia was observed in conditions without synchronizing
factors; therefore, it is assumed that the transcription response to hypoxia is endogenously
regulated [
213
]. This response was affected in mice with disrupted circadian systems, and
the time-dependent response was lost [213].
Plasticity and critical windows in prenatal development are regulated across multiple
scales, from milliseconds and minutes, controlled by neuronal oscillations, up to oscillations
with a key role of the clock genes. Moreover, plasticity windows are sensitive to circadian
gene manipulation [
222
]. These findings support the theory that the effects of prenatal
hypoxia on the foetus are time- and circadian-dependent.
Hypoxia plays an important role in developing many cardiovascular diseases, which
often exhibit the daily rhythms, and the interaction between HIFs and clock genes can
have a significant role in this process [
218
]. Relationship between the HIFs and circadian
rhythmicity was also observed in mice with myocardial infarction. Consequences of my-
ocardial infarction were circadian-dependent and varied throughout the day. Mice with
Per1
−/−
and Per2
−/−
deletion showed more severe effects than the controls with functional
clock machinery. Thus, the clock genes play an important role in regulating and expressing
HIF-target genes during hypoxic conditions [
62
]. In this line, circadian dependent program-
ming effects were observed under hyperoxic conditions during early life. Mice infected
by the influenza virus at the end of the passive phase had significantly higher mortality
Int. J. Mol. Sci. 2022,23, 2885 21 of 30
than mice infected at the end of the active phase of the day [
223
], while mice exposed to
hyperoxia during early postnatal life exhibited reduced circadian-dependent mortality due
to influenza [
224
]. This effect can be explained by a loss of circadian rhythmicity in the
lungs. It can be assumed that prenatal hypoxia acting during different times of the day may
affect the regulatory mechanisms of the cardiovascular system to different extents because
the transcription factors responding to hypoxia have different levels of expression and
activity over the 24 h period; however, all studies analysed the effect of chronic prenatal
hypoxia during the light (passive) phase in nocturnal rodents, and more studies exploring
these effects during the night are needed.
4.2.2. Consequences
Prenatal hypoxia can modulate the circadian system and thus may affect the reactivity
to challenges and susceptibility to diseases later in adulthood. Chronic prenatal hypoxia
in rats can induce changes in the circadian rhythm of locomotor activity. For example,
locomotor activity in rats prenatally exposed to hypoxia was phase-advanced, and the
animals were less active than controls [
24
]. When animals were exposed to the new light
regimen, the time required for resynchronization was prolonged in prenatally hypoxia-
affected rats, while no difference was observed during constant darkness. Thus, prenatal
hypoxia had no effects on the endogenous rhythms. This may indicate that the chronic
prenatal hypoxia affects the synchronization to environmental stimuli and the physiological
and behavioural responses to light in adulthood [
24
]. Exposure of rats to intermittent 4 h
periods of hypoxia on ED 19 and ED 20 during the daytime (passive phase for rats) increased
the blood pressure in adult male offspring but did not affect the circadian rhythms of blood
pressure and heart rate [
14
]. Similarly, prenatal hypoxia (12 h, ED 20) during the light phase
did not change the circadian rhythms of blood pressure and heart rate in male offspring,
as well as the response of the cardiovascular system to vasoconstriction drugs [
30
,
132
];
however, these animals had an altered response to artificial light at night [
132
], which is
considered as a risk factor for the disruption of circadian control and the development of
cardiovascular diseases [225].
Prenatal hypoxia can program and negatively determine the development of hyper-
tension in adulthood differently relating to the stages of prenatal development. Therefore,
knowledge of the critical developmental stages is essential because it allows for changing
the homeostatic set points and dynamic ranges of physiological systems, thus preventing
the development of hypertension in adulthood [
226
]. Many biochemical and physiological
processes develop circadian oscillations during the perinatal period. Even short-term
hypoxia during the passive phase of the day in rats can have significant effects on the
cardiovascular system in adulthood; however, there are no studies analysing the effects
of prenatal hypoxia during the active phase of the day and more studies in this field are
needed. We assume that the circadian aspects should be important for understanding the
effects of prenatal hypoxia on the cardiovascular system.
5. Conclusions
Prenatal hypoxia affects the foetal cardiovascular system, resulting in the development
of hypertension and cardiovascular diseases later in adulthood (i.e., prenatal program-
ming). The consequences of prenatal hypoxia are often associated with intrauterine growth
restriction; however, even short-term prenatal hypoxia can program hypertension of off-
spring without affecting birth body weight. As a result of prenatal hypoxia, the foetus
activates complex adaptive regulatory mechanisms, including the chemoreflex, autonomic
nervous system, NO, ROS, adenosine, catecholamines, and RAAS, which can be mod-
ulated by placental and maternal humoral factors. The placenta has a key role, and it
can compensate for a low partial pressure of oxygen, thus maintaining the demands of
the foetus. Therefore, abnormal placental development contributes to prenatal hypoxia.
Oxygen supply to the foetus is entirely dependent on the mother, and prenatal hypoxia can
also occur due to a mother’s health condition or lifestyle. The duration of hypoxia, stage of
Int. J. Mol. Sci. 2022,23, 2885 22 of 30
development, sex of progeny, and phase of the day contribute to the prenatal programming
of the cardiovascular system in adulthood. Prenatal hypoxia has more severe effects on
male offspring compared with female offspring. Until now, there is limited information on
prenatal hypoxia occurring during different times of the day on the homeostatic plasticity
of the cardiovascular system development. If the sensitivity of the developing systems
depends on the time of day, this opens new ways for understanding the mechanisms of
prenatal programming and opportunities to prevent the development of cardiovascular
hypertension in adulthood.
Author Contributions:
Bibliographic research, H.S., K.B. and L.M.; writing—review and editing,
H.S., K.B., M.Z. and L.M.; visualization, H.S., K.B. and L.M.; supervision, M.Z.; project administration,
M.Z. and L.M.; funding acquisition, M.Z.; All authors have read and agreed to the published version
of the manuscript.
Funding:
The study was supported by the Slovak Research and Development Agency (APVV-17-
0178) and the Scientific Grant Agency of the Ministry of Education of the Slovak Republic (VEGA
1/0492/19).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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