The adaptation of the cerebral circulation to pregnancy:
mechanisms and consequences
Marilyn J Cipolla
The adaptation of the cerebral circulation to pregnancy is unique from other vascular beds. Most notably, the growth and
vasodilatory response to high levels of circulating growth factors and cytokines that promote substantial hemodynamic changes in
other vascular beds is limited in the cerebral circulation. This is accomplished through several mechanisms, including
downregulation of key receptors and transcription factors, and production of circulating factors that counteract the vasodilatory
effects of vascular endothelial growth factor (VEGF) and placental growth factor. Pregnancy both prevents and reverses
hypertensive inward remodeling of cerebral arteries, possibly through downregulation of the angiotensin type 1 receptor. The
blood–brain barrier (BBB) importantly adapts to pregnancy by preventing the passage of seizure provoking serum into the brain
and limiting the permeability effects of VEGF that is more highly expressed in cerebral vasculature during pregnancy. While the
adaptation of the cerebral circulation to pregnancy provides for relatively normal cerebral blood flow and BBB properties in the face
of substantial cardiovascular changes and high levels of circulating factors, under pathologic conditions, these adaptations appear
to promote greater brain injury, including edema formation during acute hypertension, and greater sensitivity to bacterial
Journal of Cerebral Blood Flow & Metabolism (2013) 33, 465–478; doi:10.1038/jcbfm.2012.210; published online 16 January 2013
Keywords: blood–brain barrier; cerebral blood flow; cerebral circulation; pregnancy
The adaptation of the maternal cardiovascular system to
pregnancy is substantial and necessary for normal growth and
development of the fetal-placental unit.1,2Systemically, pregnancy
is a high volume, low resistance state characterized by a large
increase in cardiac output (CO) driven by circulating hormones
that rise throughout the course of gestation.1–4Plasma volume
increases 40% to 50% during singleton gestation (and up to 100%
for twin gestation) that is associated with a drop in systemic
vascular resistance.1–4As a consequence, blood pressure declines
mid-gestation then rises to normal levels near term.2,4In addition
substantial increases in blood flow during pregnancy, including
the kidneys, ovaries, and uterus.5,6The distribution of CO to
individual organs also changes over gestation with the greatest
increase to the uteroplacental circulation.6
The adaptation of the brain and cerebral circulation to
pregnancy is importantly unique from other organs because of
the need for a constant blood supply and the relative intolerance
to increased blood volume. The progressive demand on the
cardiovascular system and high levels of circulating factors that
rise over the course of pregnancy poses challenges for the brain,
an organ with high metabolic requirements and the need for tight
water and ion homeostasis. The normal physiological adaptation
of the cardiovascular system to pregnancy includes changes that
affect vessel wall integrity, hemodynamics, and coagulation that
increase the risk of stroke, edema, and other neurovascular
complications.1–4,7–9Compared with other organs, we have a
limited understanding of the adaptation of the cerebral circulation
to pregnancy and the underlying mechanisms that drive it.
However, understanding how normal pregnancy, and conditions
such as preeclampsia, affect the cerebrovascular wall is important
considering neurologic complications are a leading cause of
maternal morbidity and mortality worldwide.10
This review will describe current knowledge about the
adaptation of the cerebral circulation to pregnancy, including
changes in cerebral blood flow (CBF), hemodynamics, vascular
structure, and blood–brain barrier (BBB) properties. Although both
human and animal studies are discussed, it is worth noting that
human studies on brain blood flow and cerebrovascular structure
are difficult to perform and thus robust information on the
adaptation of the cerebral circulation in humans is lacking. We
have used animal models to characterize the adaptation of the
cerebral circulation to pregnancy and these will be described. In
addition, how the adaptation of the cerebral circulation during
pregnancy may predispose to neurologic symptoms, especially
during pathologic states such as preeclampsia and eclampsia, is
CHANGES IN CEREBRAL BLOOD FLOW AND AUTOREGULATION
DURING NORMAL PREGNANCY
Measurement of Cerebral Blood Flow and Cerebrovascular
Resistance During Pregnancy
The substantial increase in plasma volume and CO during
pregnancy is distributed unequally to several organ systems.
Most notably, uterine blood flow increases 10-fold over the
nonpregnant state by late-gestation, with the percent of CO
Departments of Neurological Sciences, Obstetrics, Gynecology and Reproductive Sciences, Pharmacology, University of Vermont College of Medicine, Burlington, Vermont, USA.
Correspondence: Dr MJ Cipolla, Department of Neurological Sciences, University of Vermont College of Medicine ,149 Beaumont Avenue, HSRF 416A, Burlington, VT 05405, USA.
This study was supported by NINDS Grants RO1 NS045940, RO1 NS045940-05S1, RO1 NS045940-6S1, NHLBI Grant PO1 095488, and the Totman Trust for Medical Research.
Received 26 October 2012; revised 2 December 2012; accepted 8 December 2012; published online 16 January 2013
Journal of Cerebral Blood Flow & Metabolism (2013) 33, 465–478
& 2013 ISCBFMAll rights reserved 0271-678X/13 $32.00
received by the uteroplacental unit increasing from B0.5% to
15%.5,6Undoubtedly, such a dramatic increase in CBF cannot
be tolerated by the brain. However, the magnitude by which
CBF does change during pregnancy, if at all, has been difficult to
assess in humans. Transcranial Doppler (TCD) ultrasound has
been widely used to study cerebral hemodynamics during
human pregnancy because it is noninvasive and can measure
changes in blood flow velocity.11–15However, it cannot measure
vessel diameter and thus the validity of extrapolating CBF
crosssectional study used dual-beam angle-independent digital
ultrasound to measure blood flow changes in the internal carotid
artery (ICA) over the course of pregnancy in healthy women.17
This study also measured ICA diameter and thus calculated
changes in cerebrovascular resistance (CVR) and global CBF. In
this study, CVR decreased from a nonpregnant value of 0.141
to 0.112mmHg?mL/100g/min in the third trimester, with CBF
increasing22% from 42.2mL/100g/min
women to 51.8mL/100g/min in the third trimester. The strength
of this study is that ICA diameter and blood flow volume
were measured; however, it is limited by a crosssectional analysis
and that there were eightfold more patients measured in the
more than in the first trimester. In addition, how the authors
normalized to brain weight is unclear. The finding that CBF
increases 22% by late-gestation is in contrast to a longitudinal
study by Zeeman et al,18who used velocity encoded magnetic
resonance imaging of the middle cerebral and posterior cerebral
arteries (PCA) in 10 pregnant women and found CBF decreased by
20% in the third trimester. However, this study used postpartum
values for comparison that may not be as appropriate as
prepregnancy values. The discrepancy in CBF values reported in
these studies highlight the difficultly in measuring CBF in
We and others have used microspheres in animals to measure
absolute changes in CBF during pregnancy.6,19,20There are
obvious limitations to animal studies as well, including the use
of anesthesia in some19,20but not all6studies that can affect CVR
and CBF. Further, the use of microspheres is terminal, thus
precluding longitudinal studies. In unanesthetized, standing sheep
instrumented with indwelling catheters, CBF was found to
decrease from 48mL/100g/min in the nonpregnant state to
38mL/100g/min by late-pregnancy (130 to 140 days).6Other
studies in anesthetized rats found little change in CBF at late-
gestation compared with nonpregnant: 92 versus 88mL/100g/
min19and 58 versus 60mL/100g/min.20
Measurement of Autoregulation of Cerebral Blood Flow During
Autoregulation of CBF is an important mechanism that provides
relatively constant blood supply during changes in perfusion
pressure. It is a highly protective mechanism in the brain that
has limits. In normotensive adults, CBF is B50mL/100g/min
provided that cerebral perfusion pressure is between B60
Above and below these limits, CBF
becomes dependent on perfusion pressure linearly. During
normal pregnancy, cerebral autoregulation appears to be intact
and similar to nonpregnant women, as assessed by transient
hyperemic response and TCD.24However, whether or not the
limits of autoregulation are shifted during human pregnancy is
not known, but important to understand considering both
hypertensive and hypotensive episodes occur frequently in
pregnant women. For example, hypertension is one of the
most common complications of pregnancy.25If the upper limit
ofautoregulation is shifted
pregnancy, autoregulatory breakthrough would occur at lower
pressures, potentially causing vasogenic edema. In fact, edema
to lowerpressures during
formation in response to autoregulatory breakthrough has
been proposed as an underlying mechanism of eclampsia.10,26,27
The lower limit of CBF autoregulation is also important to
understand because substantial hemorrhage occurs during
parturition often lowering blood pressure.28If the lower limit of
autoregulation is shifted to higher pressures, CBF may fall with
decreasing pressure, leading to neurological symptoms such as
dizziness, confusion, loss of consciousness, and ultimately
ischemic brain damage.29–31
We have measured the limits of CBF autoregulation during
normal pregnancy in anesthetized rats using laser Doppler to
measure changes in CBF. Using pentobarbital as an anesthetic
with acute infusion of phenylephrine to raise blood pressure, we
found no difference in the pressure at which autoregulatory
breakthrough occurred between nonpregnant and late-pregnant
rats.32However, because laser Doppler measures relative changes
in CBF, whether or not CBF was at the same level after
determined. Thus, in a separate study we used microspheres to
measure absolute changes in CBF basally before infusion of
phenylephrine and then after blood pressure was acutely
increased to 203±3mmHg for nonpregnant and 193±3mmHg
for late-pregnant rats. We found that while CBF was similar in late-
pregnant versus nonpregnant rats at baseline, there was an
B40% increase in CBF with acute hypertension in the pregnant
animals (Figure 1A).20The increase in CBF at the higher
pressures was due to a decrease in CVR that was greater in
the pregnant animals: 0.70±0.07mmHg?mL/100g/min for
pregnant (Figure 1B). The decreased CVR in pregnant animals
with acute hypertension is likely due to increased vascular volume
that occurs in pregnancy secondary to outward remodeling of
brain arterioles and increased capillary density (see below).
Autoregulation of CBF was recently measured in nonpregnant
and late-pregnant rats using chloral hydrate anesthesia instead of
autoregulation is somewhat shifted to higher pressures in late-
pregnant rats in both the anterior and posterior cerebral cortices
(Figures 2A and 2B). However, the shape of the CBF autoregulatory
curves is different with the different anesthesia, likely because
chloral hydrate did not produce the same change in CBF,
suggesting that there was some decrease in CVR compared with
pentobarbital before the start of phenylephrine infusion. Regard-
less, when brain water content was measured, only the pregnant
animals had significant edema formation in response to acute
hypertension, similar to pentobarbital anesthesia.20,33Thus, it
appears that the brain is more susceptible to edema formation
during pregnancy when there is an acute elevation in blood
pressure. This finding is significant considering edema is a primary
mechanism by which seizure is thought to occur during
In addition to shifting the upper limit of CBF autoregulation,
pregnancy also appears to shift the lower limit. Cerebral blood
flow autoregulation during hemorrhagic hypotension was mea-
sured in nonpregnant and late-pregnant rats under chloral
hydrate anesthesia. Unlike the upper limit of CBF autoregulation
that was shifted in both anterior and posterior cerebral
cortices during pregnancy, the lower limit of autoregulation was
shifted to lower pressures only in the posterior cerebral cortex
(Figures 2C and 2D). The extension of the autoregulatory curve
to lower pressures during pregnancy may be a protective
mechanism against hypoxia/ischemia during hemorrhagic hypo-
tension that occurs during parturition. The mechanism by which
this occurs preferentially in the posterior cortex, or the conse-
quence thereof, is not completely understood. However, gesta-
tion-induced changes in endothelial and neuronal nitric oxide
synthase (eNOS and nNOS) specifically in the posterior cerebral
cortex may have a role.33
occurred could notbe
that theupper limitof
Cerebrovascular adaptation to pregnancy
Journal of Cerebral Blood Flow & Metabolism (2013), 465–478
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45 Chillon J-M, Ghoniem S, Baumbach GL. Effects of chronic nitric oxide
synthase inhibition on cerebral arterioles in rats. Hypertension 1997; 30:
46 Barry DI, Strandgaard S, Graham DI, Braendstrup O, Svendsen UG, Vorstrup S
et al. Cerebral blood flow in rats with renal and spontaneous hypertension:
resetting of the lower limit of autoregulation. J Cereb Blood Flow Metab 1982; 2:
47 Heistad DD, Baumbach GL. Cerebral vascular changes during chronic hyper-
tension: good guys and bad guys. J Hypertens 1992; 10(Suppl 7): S71–S75.
48 Fujishima M, Ibayashi S, Fujii K, Mori S. Cerebral blood flow and brain function in
hypertension. Hypertens Res 1995; 18: 111–117.
49 Cipolla MJ, DeLance N, Vitullo L. Pregnancy prevents hypertensive remodeling of
cerebral arteries: a potential role in the development of eclampsia. Hypertension
2006; 47: 619–626.
50 Aukes AM, Vitullo L, Zeeman G, Cipolla MJ. Pregnancy prevents hypertension-
induced remodeling and diminishes myogenic reactivity of posterior cerebral
arteries in Dahl Salt Sensitive rats: role in eclampsia? Am J Physiol 2007; 292:
51 Chan S-L, Chapman AC, Godfrey JA, Gokina N, Cipolla MJ. Effect of PPARg
inhibition during pregnancy on posterior cerebral artery function and structure.
Frontiers Physiol 2010; 1: 130.
52 Cipolla MJ, Smith J, Bishop N, Bullinger LV, Godfrey JA. Pregnancy reverses
hypertensive remodeling of cerebral arteries. Hypertension 2008; 51: 1052–1057.
53 Berger JP, Akiyama TE, Meinke PT. PPARs: therapeutic targets for metabolic
disease. Trends Pharmacol Sci 2005; 26: 244–251.
54 Hsueh WA, Law RE. PPARgamma and atherosclerosis: effects on cell growth and
movement. Arterioscler Thromb Vasc Biol 2001; 21: 1891–1895.
55 Robinson E, Grieve DJ. Significance of peroxisome proliferator-activated recep-
tors in the cardiovascular system in health and disease. Pharmacol Ther 2009;
56 Sigmund CD. Endothelial and vascular muscle PPARgamma in arterial pressure
regulation: lessons from genetic interference and deficiency. Hypertension 2010;
57 Waite LL, Person EC, Zhou Y, Lim KH, Scanlan TS, Taylor RN. Placental peroxisome
proliferator-activated receptor-gamma is up-regulated by pregnancy serum.
J Clin Endocrinol Metab 2000; 85: 3808–3814.
58 Wieser F, Waite L, Depoix C, Taylor RN. PPAR action in human placental devel-
opment and pregnancy and its complications. PPAR Res 2008 527048.
59 Takeda K, Ichiki T, Tokunou T, Funakoshi Y, Iino N, Hirano K et al. Peroxisome
proliferator-activated receptor gamma activators downregulate angiotensin II
type 1 receptor in vascular smooth muscle cells. Circulation 2000; 102:
60 Benkirane K, Amiri F, Diep QN, Mabrouk EI, Schiffrin EL. PPAR-gamma inhibits
ang II-induced cell growth via SHIP2 and 4E-BP1. Am J Physiol 2006; 290:
61 Beyer AM, de Lange WJ, Halabi CM, Modrick ML, Keen HL, Faraci FM et al.
Endothelium-specific interferencewith peroxisome
receptor gamma causes cerebral vascular dysfunction in response to a high-fat
diet. Circ Res 2008; 103: 654–661.
62 Beyer AM, Baumbach GL, Halabi CM, Modrick ML, Lynch CM, Gerhold TD et al.
Interference with PPARgamma signaling causes cerebral vascular dysfunction,
hypertrophy, and remodeling. Hypertension 2008; 51: 867–871.
63 Halabi CM, Beyer AM, de Lange WJ, Keen HL, Baumbach GL, Faraci FM et al.
Interference with PPAR gamma function in smooth muscle causes vascular
dysfunction and hypertension. Cell Metab 2008; 7: 215–226.
64 Novak J, Danielson LA, Kerchner LJ, Sherwood OD, Ramirez RJ, Moalli PA et al.
Relaxin is essential for renal vasodilation during pregnancy in conscious rats. J
Clin Invest 2001; 107: 1469–1475.
65 Singh S, Bennett RG. Relaxin signaling activates peroxisome proliferator-acti-
vated receptor gamma. Mol Cell Endocrinol 2010; 315: 239–245.
66 Chan S-L, Cipolla MJ. Relaxin activates PPARg and causes selective outward
remodeling of brain penetrating arterioles. FASEB J 2011; 25: 3229–3239.
67 Bleys RL, Cowen T. Innervation of cerebral blood vessels: morphology, plasticity,
age-related, and Alzheimer’s disease-related neurodegeneration. Microsc Res
Tech 2001; 53: 106–118.
68 Sa ´ndor P. Nervous control of the cerebrovascular system: doubts and facts.
Neurochem Int 1999; 35: 237–259.
69 Morita Y, Hardebo JE, Bouskela E. Influence of cerebrovascular sympathetic,
parasympathetic, and sensory nerves on autoregulation and spontaneous
vasomotion. Acta Physiol Scand 1995; 152: 121–130.
70 Bill A, Linder J. Sympathetic control of cerebral blood flow in acute arterial
hypertension. Acta Physiol Scand 1976; 96: 114–121.
71 Beausang-Linder M, Bill A. Cerebral circulation in acute arterial hypertension--
protective effects of sympathetic nervous activity. Acta Physiol Scand 1981; 11:
72 Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA. Intrinsic brain
activity triggers trigeminal meningeal afferents in a migraine model. Nat Med
2002; 8: 136–142.
73 Goadsby PJ. Recent advances in understanding migraine mechanisms, mole-
cules and therapeutics. Trends Mol Med 2007; 13: 39–44.
74 Hargreaves R. New migraine and pain research. Headache 2007; 47(Suppl 1):
75 Sibai BM. Diagnosis, prevention, and management of eclampsia. Obstet Gynecol
2005; 105: 402–410.
76 Aukes AM, Bishop N, Godfrey JA, Cipolla MJ. The effect of pregnancy and gender
on perivascular innervartion of rat posterior cerebral arteries. Reprod Sci 2007;
77 Gupta S, Mehrotra S, Villalo ´n CM, Perusquı ´a M, Saxena PR, MaasenVanDenBrink
A. Potential role of female sex hormones in the pathophysiology of migraine.
Pharmacol Ther 2007; 113: 321–340.
78 An H, Lin W. Cerebral venous and arterial blood volumes can be estimated
separately in humans using magnetic resonance imaging. Magn Reson Med
2002; 48: 583–588.
79 Anile C, De Bonis P, Di Chirico A, Ficola A, Mangiola A, Petrella G. Cerebral blood
flow autoregulation during intracranial hypertension: a simple, purely hydraulic
mechanism? Childs Nerv Syst 2009; 25: 325–335.
80 Mandeville JB, Marota JJ, Kosofsky BE, Keltner JR, Weissleder R, Rosen BR et al.
Dynamic functional imaging of relative cerebral blood volume during rat fore-
paw stimulation. Magn Reson Med 1998; 39: 615–624.
81 Kato Y, Mokry M, Pucher R, Auer LM. Cerebrovascular response to changes of
cerebral venous pressure and cerebrospinal fluid pressure. Acta Neurochir (Wien)
1991; 109: 52–56.
82 Saposnik G, Barinagarrementeria F, Brown Jr. RD, Bushnell CD, Cucchiara B,
Cushman M et al. Diagnosis and management of cerebral venous thrombosis: a
statement for healthcare professionals from the American Heart Association/
American Stroke Association. Stroke 2011; 42: 1158–1192.
83 Cantu C, Barinagarrementeria F. Cerebral venous thrombosis associated with
pregnancy and puerperium. Review of 67 cases. Stroke 1993; 24: 1880–1884.
84 Tate J, Bushnell C. Pregnancy and stroke risk in women. Women’s Health
(Lond Engl) 2011; 7: 363–374.
85 van der Wijk A-E, Schreurs MP, Cipolla MJ. Pregnancy causes diminished
myogenic tone and outward hypotrophic remodeling of the cerebral vein of
Galen. J Cerebr Blood Flow Metab advance online publication, 2 January 2013;
doi:10.1038/jcbfm.2012.199 (in press).
86 Schmidek HH, Auer LM, Kapp JP. The cerebral venous system. Neurosurgery 1985;
87 Zlokovic B. The blood-brain barrier in health and chronic neurodegenerative
disorders. Neuron 2008; 57: 178–201.
88 Kimelberg HK. Water homeostasis in the brain: basic concepts. Neuroscience
2004; 129: 851–860.
89 Zygmunt M, Herr F, Munstedt K, Lang U, Liang OD. Angiogenesis and vasculo-
genesis in pregnancy. Eur J Obstet Gynecol Reprod Biol 2003; 110(Suppl 1):
90 Valdes G, Erices R, Chacon C, Angiogenic CorthornJ. Hyperpermeability and
vasodilator network in utero-placental units along pregnancy in the guinea-pig
(Cavia porcellus). Reprod Biol Endocrinol 2008; 6: 13.
91 Valdes G, Corthorn J. Review: the angiogenic and vasodilatory utero-placental
network. Placenta 2011; 32(Suppl 2): S170–S175.
92 Euser AG, Bullinger LV, Cipolla MJ. Magnesium sulfate decreases blood-brain
barrier permeability during acute hypertension in pregnant rats. Exp Physiol
2008; 93: 254–261.
93 Butt AM, Jones HC, Abbott NJ. Electrical resistance across the blood-brain
barrier in anaesthetized rats: a developmental study. J Physiol 1990; 429:
94 Schreurs M, Houston E, May V, Cipolla MJ. The adaptation of the blood-brain
barrier to VEGF and PLGF during pregnancy. FASEB J 2012; 26: 355–362.
95 Cipolla MJ, Pusic AD, Grinberg YY, Chapman AC, Houston EM, Poynter ME et al.
Pregnant serum causes neuroinflammation and seizure activity via TNFa. Exp
Neurol 2012; 234: 398–404.
96 Amburgey OA, Chapman AC, May V, Bernstein IM, Cipolla MJ. Plasma from
preeclamptic women increases blood-brain barrier permeability: role of vascular
endothelial growth factor signaling. Hypertension 2010; 56: 1003–1008.
97 Evans P, Wheeler T, Anthony F, Osmond C. Maternal serum vascular endothelial
growth factor during early pregnancy. Clin Sci (Lond) 1997; 92: 567–571.
98 Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling - in
control of vascular function. Nat Rev Mol Cell Biol 2006; 7: 359–371.
99 Mayhan WG. VEGF increases permeability of the blood-brain barrier via a nitric
100 Breen EC. VEGF in biological control. J Cell Biochem 2007; 102: 1358–1367.
Cerebrovascular adaptation to pregnancy
& 2013 ISCBFMJournal of Cerebral Blood Flow & Metabolism (2013), 465–478
101 Celia G, Osol G. Mechanism of VEGF-induced uterine venous hyperpermeability.
J Vasc Res 2005; 42: 47–54.
102 Espinoza J, Uckele JE, Starr RA, Seubert DE, Espinoza AF, Berry SM. Angiogenic
imbalances: the obstetric perspective. Am J Obstet Gynecol 2010; 203: e11–e18.
103 Young BC, Levine RJ, Karumanchi SA. Pathogenesis of preeclampsia. Annu Rev
Pathol 2010; 5: 173–192.
104 D’Mello C, Le T, Swain MG. Cerebral microglia recruit monocytes into the brain in
response to tumor necrosis factor alpha signaling during peripheral organ
inflammation. J Neurosci 2009; 29: 2089–2102.
105 Sacks GP, Studena K, Sargent K, Redman CW. Normal pregnancy and pre-
eclampsia both produce inflammatory changes in peripheral blood leukocytes
akin to those of sepsis. Am J Obstet Gynecol 1998; 179: 80–86.
106 Szarka A, Rigo ´ Jr J, La ´za ´r L, Beko G, Molvarec A. Circulating cytokines, chemo-
kines and adhesion molecules in normal pregnancy and preeclampsia deter-
mined by multiplex suspension array. BMC Immunol 2010; 11: 59.
107 Riazi K, Galic MA, Kuzmiski JB, Ho W, Sharkey KA, Pittman QJ. Microglial acti-
vation and TNFalpha production mediate altered CNS excitability following
peripheral inflammation. Proc Natl Acad Sci USA 2008; 105: 17151–17156.
108 Katz VL, Farmer R, Kuller JA. Preeclampsia into eclampsia: toward a new para-
digm. Am J Obstet Gynecol 2000; 182: 1389–1396.
109 Sabai BM. Eclampsia. VI. Maternal-perinatal outcome in 254 consecutive cases.
Am J Obstet Gynecol 1990; 163: 1049–1055.
110 AIshibashi K, Kuwahara M, Sasaki S. Molecular biology of aquaporins. Rev Physiol
Biochem Pharmacol 2000; 141: 1–32.
111 Agre P, Bonhivers M, Borgnia MJ. The aquaporins, blueprints for cellular
plumbing systems. J Biol Chem 1998; 273: 14659–14662.
112 Verkman AS. Aquaporin water channels and endothelial cell function. J Anat
2002; 200: 617–627.
113 Amiry-Moghaddam M, Ottersen OP. The molecular basis of water transport in
the brain. Nature Rev Neurosci 2003; 4: 991–1001.
114 Hasegawa H, Ma T, Skach W, Matthay MA, Verkman AS. Molecular cloning of a
mercurial-insensitive water channel expressed in selected water-transporting
tissues. J Biol Chem 1994; 269: 5497–5500.
115 Jung JS, Bhat RV, Preston GM, Guggino WB, Baraban JM, Agre P.
Molecular characterization of an aquaporin cDNA from brain: candidate
osmoreceptor and regulator of water balance. Proc Natl Acad Sci USA 1994; 91:
116 Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OP.
Specialized membrane domains for water transport in glial cells: High-resolution
immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci 1997; 17:
117 Amiry-Moghaddam M, Otuska T, Hurn PD, Traystman RJ, Haug F-M, Froehner SC
et al. An alpha-syntrophindependent pool of AQP4 in astroglial end-feet confers
bidirectional water flow between blood and brain. Proc Natl Acad Sci USA 2003;
118 Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW et al. Aquaporin-4
deletion in mice reduces brain edema after acute water intoxication and
ischemic stroke. Nat Med 2000; 6: 159–163.
119 Quick AM, Cipolla MJ. Pregnancy-induced upregulation of aquaporin-4 protein
in brain and its role in eclampsia. FASEB J 2005; 19: 170–175.
120 Wiegman MJ, Bullinger LV, Kholmeyer M, Hunter TC, Cipolla MJ. Regional
expression of aquaporin -1, -4 and -9 in the brain during pregnancy. Reprod Sci
2008; 15: 506–516.
121 Binder DK, Oshio K, Ma T, Verkman AS, Manley GT. Increased seizure threshold in
mice lacking aquaporin-4 water channels. Neuroreport 2004; 15: 259–262.
Cerebrovascular adaptation to pregnancy
Journal of Cerebral Blood Flow & Metabolism (2013), 465–478
& 2013 ISCBFM