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Original Research Article
Dietary adenosine supplementation improves placental angiogenesis
in IUGR piglets by up-regulating adenosine A2a receptor
Zifang Wu
a
,
1
, Jiawei Nie
a
,
1
, Deyuan Wu
a
, Shuangbo Huang
a
, Jianzhao Chen
a
,
Huajin Liang
a
, Xiangyu Hao
a
, Li Feng
a
, Hefeng Luo
b
,
*
, Chengquan Tan
a
,
*
a
Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, Institute of
Subtropical Animal Nutrition and Feed, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
b
Dekon Food and Agriculture Group, Chengdu, China
article info
Article history:
Received 28 April 2022
Received in revised form
9 December 2022
Accepted 15 February 2023
Available online 22 February 2023
Keywords:
Angiogenesis
IUGR
Placenta
Adenosine
ADORA2A
abstract
Abnormal placental angiogenesis is associated with the occurrence of intrauterine growth restriction
(IUGR) in piglets, and effective treatment strategies against this occurrence remain to be explored.
Adenosine has been reported to play an important role in angiogenesis, but its role in placental angio-
genesis is still unknown. Here, we investigated the effect of dietary adenosine supplementation on IUGR
occurrence in piglets by analyzing the role of adenosine in placental angiogenesis for Normal and IUGR
piglets. Specifically, 88 sows were allotted to 2 treatments (n¼44) and fed a basal diet supplemented
with 0% or 0.1% of adenosine from day 65 of gestation until farrowing, followed by collecting the
placental samples of Normal and IUGR piglets, and recording their characteristics. The results showed
that adenosine supplementation increased the mean birth weight of piglets (P<0.05) and placental
efficiency (P<0.05), while decreasing the IUGR piglet rate (P<0.05). Expectedly, the placenta for IUGR
neonates showed a down-regulated vascular density (P<0.05) and angiogenesis as evidenced by the
expression level of vascular cell adhesion molecule-1 (VCAM1) (P<0.05). Notably, dietary adenosine
supplementation promoted angiogenesis (P<0.05) both in the Normal and IUGR placenta. More
importantly, the expression level of adenosine A2a receptor (ADORA2A) was lower (P<0.05) in the IUGR
placenta than in Normal placenta, whereas adenosine treatment could significantly increase ADORA2A
expression, and also had an interaction effect between factors IUGR and Ado. Collectively, placentae for
IUGR piglets showed impaired angiogenesis and down-regulated expression level of ADORA2A, while
dietary adenosine supplementation could activate ADORA2A expression, improve the placental angio-
genesis, and ultimately decrease the occurrence of IUGR in piglets.
©2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
1. Introduction
As a complication of pregnancy, intrauterine growth restriction
(IUGR) can cause a low birth weight (LBW) for neonates, and about
15% to 25% of piglets were reported to suffer from IUGR in pig
production (Freking et al., 2016). IUGR can bring a series of adverse
consequences to piglets, such as a higher rate of morbidity and
mortality, slower growth rate, as well as abnormal organ devel-
opment (Oksbjerg et al., 2013;Wu et al., 2006), suggesting a
beneficial effect of reducing IUGR rate on the reproductive effi-
ciency of sows. However, the mechanism underlying IUGR occur-
rence is still largely unclear.
It is essential for the placenta to efficiently transfer oxygen and
nutrients from the mother to the fetus to maintain normal fetal
*Corresponding authors.
E-mail addresses: sixfires@126.com (H. Luo), tanchengquan@scau.edu.cn
(C. Tan).
1
These authors contributed equally to this work.
Peer review under responsibility of Chinese Association of Animal Science and
Veterinary Medicine.
Production and Hosting by Elsevier on behalf of KeAi
Contents lists available at ScienceDirect
Animal Nutrition
journal homepage: http://www.keaipublishing.com/en/journals/aninu/
https://doi.org/10.1016/j.aninu.2023.02.003
2405-6545/©2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Animal Nutrition 13 (2023) 282e288
growth, and the blood vessels in the placenta play an important
role in the exchange of maternalefetal material (Reynolds et al.,
2006;Sun et al., 2020;Zhang et al., 2022). Previous studies
revealed abnormal angiogenesis in LBW placenta (Hu et al., 2021;
Huang et al., 2021a), implying that improving angiogenesis in the
placenta might decrease IUGR occurrence. As an endogenous pu-
rine nucleoside, adenosine exerts its biological effects by activating
its 4 adenosine receptor subtypes, including adenosine A1 receptor
(ADORA1); adenosine A2a receptor (ADORA2A); adenosine A2b
receptor (ADORA2B) and adenosine A3 receptor (ADORA3) (Salsoso
et al., 2017). Previous studies have confirmed the promoting role of
adenosine in biological and pathological angiogenesis (Antonioli
et al., 2021;Troncoso et al., 2020;Valls et al., 2021). Additionally,
adenosine was reported to activate ADORA2A to potentiate angio-
genesis by regulating the levels of angiogenesis factors including
vascular endothelial growth factor (VEGF) and hypoxia inducible
factor-1
a
(HIF-1
a
)(Escudero et al., 2013;Fernandez et al., 2012;Liu
et al., 2017). However, the effect of adenosine on placental angio-
genesis remains to be further investigated.
In this study, adenosine was assumed to alleviate IUGR occur-
rence by enhancing placental angiogenesis, and this hypothesis was
tested by analyzing the effects of adenosine on the occurrence of
IUGR piglets and comparing the angiogenesis and the expression of
adenosine receptors in placentae for Normal and IUGR piglets.
2. Materials and methods
2.1. Animal ethics statement
All animal experimental design and procedures presented in
this study were approved by the Animal Care and Use Committee of
the Institute of Subtropical Agriculture, Chinese Academy of Sci-
ence, and performed according to the Guidelines for Care and Use
of Laboratory Animals of South China Agriculture University
(Guangzhou, China).
2.2. Animals and experimental design
The sows used in this study were obtained from Jiangxi Wan-
nian Xinxing Agro-pastoral Co., Ltd., China. A total of 88
Duroc Landrace Yorkshire sows were divided into 2 dietary
treatment groups, each sow as a replicate of a completely ran-
domized design, based on the body weight at day 65 of gestation
(n¼44 per treatment). From day 65 of gestation to farrowing, the
control group (Con) sows were fed a basal gestation diet without
adenosine supplementation, while the adenosine group (Ado) sows
were fed a basal diet with 0.1% adenosine supplementation.
Adenosine was from Hangzhou Kaipeng Biotechnology Co., Ltd.,
Hangzhou, China, purity (HPLC) 98.0%. Both diets were formu-
lated to meet the National Research Council (NRC, 2012) nutritional
standards for gestational sows. The composition of the diet is
shown in Supplementary Table S1. The feed intake of the sows is
shown in Supplementary Table S2.
2.3. Data collection and sampling
After farrowing, the number and weight of piglets born were
recorded. The IUGR rate was calculated as previously described
(Aditya et al., 2016). Briefly, IUGR piglets were defined as piglets
with a birth weight of 2 standard deviations lower than the mean
birth weight of the Con group piglets. When piglets were born, the
umbilical cord was immediately tied with a silk line (labeled with a
number tag to indicate the birth order of the piglet), and each piglet
was marked with a numbered tag to match the placenta. The
newborn piglet birth weight and numerical order were recorded,
the placenta weight was also recorded after placental expulsion.
Then, approximately 10 g of the placenta (3 to 4 cm from the cord
insertion point) was collected and snap-frozen immediately in
liquid nitrogen, and another fresh placental tissue was collected
and fixed in 4% paraformaldehyde immediately. The placental ef-
ficiency was calculated by dividing piglet weight by placental
weight (Wilson et al.,1999). The average birth weight of 441 piglets
in the Con group in this study was 1.37 ±0.15 kg (mean ±SD), and
the placental samples were divided into 2 groups according to
piglet birth weight: <1.07 kg (IUGR) and 1.37 to 1.52 kg (Normal).
Six sows were randomly selected from each group, and each sow
was randomized to provide 1 placenta of Normal fetal (piglet with
birth weight 1.37 to 1.52 kg) and 1 placenta of IUGR fetal (piglet
with birth weight <1.07 kg) for following analysis.
2.4. Placental vascular density
Six sows were selected from each group, and 2 placental samples
of each sow were analyzed, including 1 Normal and 1 IUGR placental
sample. By image analysis, the number of blood vessels was deter-
mined by estimating the mean value of 3 slices of 1 placenta. Briefly,
fresh placental tissues fixed in 4% paraformaldehyde were paraffin-
embedded and sectioned at 5
m
m thickness, then stained with he-
matoxylin and eosin (H&E). The areas occupied by placental tissues
and the placental vessels in these areas were traced with a projec-
ting microscope (Olympus CX41, Japan). For each of the 5
m
m sec-
tions, the total number of vessels in the placental stromal areas were
determined and then corrected for the measured total placental
stromal areas (per unit area as mm
2
).
2.5. Quantitative real-time RT-PCR analysis
Total RNA from placental tissues was extracted with the reagent
box of a Tissue RNA Purification Kit (EZBioscience, Suzhou, China)
as instructed by the manufacturer. The concentration of RNA was
quantified using a NanoDrop-2000 (Thermo Fisher, USA). After
reverse transcription using a Color Reverse Transcription Kit
(EZBioscience, Suzhou, China), qRT-PCR was conducted using SYBR
Green on a QuantStudio 6 RealTime PCR System (Thermo Fisher,
USA) under the conditions of denaturation at 95
C for 10 min,
amplification at 95
C for 15 s and 60
C for 1 min for 40 cycles. Each
target gene was individually normalized to the reference gene 18S
rRNA by using the quantification method of 2
DD
ct
. Primers used in
this study are shown in Supplemental Table S3.
2.6. Western blotting
Total proteins were extracted from placental tissues using a
protein extraction kit (Beyotime, Beijing, China) as informed by the
manufacturer. Briefly, 10
m
g of protein was loaded and separated by
SDS-PAGE gel electrophoresis, and then the protein was transferred
onto a polyvinylidene difluoride membrane (Merck Millipore). Af-
ter blocking with TBST buffer containing 5% milk, the blots were
then incubated overnight at 4
C with each of the following primary
antibodies: angiogenin (Ang) (ab95389, abcam, 1:1000), ADORA1
(ab82477, abcam, 1:1000), ADORA2A (ab3461, abcam, 1:1000),
ADORA2B (ab222901, abcam, 1:1000), ADORA3 (ab197350, abcam,
1:1000), vascular endothelial growth factor A (VEGF-A) (19003-1-
AP, Proteintech, USA, 1:1000), Akt (9272, CST, 1:1000), p-Akt
(4060, CST, 1:1000), signal transducer and activator of
transcription-3 (Stat3) (ab76315, Abcam, USA, 1:1500), p-Stat3
(ab68153, Abcam, USA, 1:1500), vascular cell adhesion molecule-1
(VCAM1) (ab134047, abcam, 1:1000), and
b
-actin (4970, CST, USA,
1:1000). Subsequently, the membranes were incubated with
appropriate HRP-conjugated anti-rabbit IgG secondary antibody
Z. Wu, J. Nie, D. Wu et al. Animal Nutrition 13 (2023) 282e288
283
(AS014, Abclonal, China, 1:5000). Images were captured using the
ChemiDoc MP system (Bio-Rad, Hercules, CA, USA), and band
densities were quantified using Image Lab soft-ware (Bio-Rad,
Hercules, CA, USA) and then normalized to
b
-actin content.
2.7. Immunofluorescence
Placental tissues immobilized in 4% paraformaldehyde were
embedded in paraffin and sectioned at 5
m
m thickness for platelet
endothelial cell adhesion molecule-1 (CD31) and ADORA2A
immunofluorescence. Slides were visualized under a fluorescent
microscope (Nikon Eclipse C1, Tokyo, Japan) and quantified by
ImageJ software.
2.8. Statistical analysis
All data were presented with bar charts using GraphPad Prism
(GraphPad Software, La Jolla, CA) and each bar represents the
mean ±standard error of the mean (SEM). For sow and litter data,
the sow or the litter represented the experimental unit. Statistical
significance of reproductive performance (piglet mean BW at birth
and placental efficiency) was determined by unpaired Student's t-
test using SPSS 20.0 (SPSS Inc., Chicago, USA) software. The IUGR
rate was analyzed using the Chi-square test. Data from 6 duplicate
placental samples were analyzed as a 2 2 factorial treatment
arrangement using the general linear model procedure of SAS (SAS
Inst. Inc., Cary, NC, USA) unless otherwise specified (also analyzed
using unpaired Student's t-test). The model utilized included the
main factors of piglet birth weight (factor 1 ¼IUGR), adenosine
supplementation (factor 2 ¼Ado) and their interaction
(IUGR Ado). Differences were considered significant at P<0.05,
and a tendency was considered at 0.05 P<0.1.
3. Results
3.1. Characteristics of piglets
As shown in Fig. 1, the Ado group was higher than the Con group
for piglet mean birth weight (P<0.001) and placental efficiency
(P<0.01) (Fig. 1A and B), but had a lower IUGR rate (P<0.01)
(Fig. 1C).
3.2. Placental vessel density
Fig. 2 shows the immunostaining results of placental vascular
density and VCAM1 expression in Normal and IUGR fetuses in the
Con and Ado groups. As shown in the figure, the placenta from
normal piglets had higher placental vascular density (P<0.01) and
VCAM1 expression (P<0.01) compared to the placenta from IUGR
piglets. Adenosine treatment also increased the placental vascular
density (P<0.01) and the expression level of VCAM1 (P<0.01).
Moreover, an interaction effect was observed between IUGR and
Ado in their effect on VCAM1 expression (P<0.01).
3.3. mRNA abundance of placental angiogenesis
The effects of adenosine and birth weight of newborn piglets
on placental angiogenesis were further explored by analyzing the
mRNA expression of angiogenesis-related genes. A total of 7
angiogenesis-related genes were evaluated by qRT-PCR (Fig. 3).
The IUGR placenta had a marked decrease in the mRNA
expression of VEGF-A (P<0.01) and TGF-1
b
(P<0.05). The
adenosine treatment had an up-regulated trend in the mRNA
expression of Ang (P¼0.06). Moreover, an interaction effect was
observed in VEGF-A and TGF-1
b
mRNA expression between IUGR
and Ado (P<0.05). Interestingly, in t-test analysis, the mRNA
levels of VEGF-A and Ang in the IUGR placenta were decreased
compared to the Normal placenta in the Con group (P<0.05),
and had a rescued trend in adenosine treatment (P¼0.07 and
P¼0.08). However, in normal placenta, there was no difference
in the mRNA levels of VEGF-A and Ang in adenosine treatment
(P>0.05).
3.4. Expression of adenosine receptors in placenta
Next, the expression level of adenosine receptors in the
placenta for IUGR and normal piglets were evaluated. As shown in
Fig. 4AeD, the IUGR factor had no significant effect on mRNA
levels of placental adenosine receptors, but the ADORA2A
expression level was decreased in the IUGR placenta in immu-
nostaining analysis (P<0.01). In addition, the mRNA expression of
both ADORA2A (P<0.01) and ADORA2B (P<0.05) revealed an
increase with adenosine treatment, and similar results were also
found in immunostaining analysis in that the expression level of
ADORA2A was increased with adenosine treatment (P<0.01)
(Fig. 4E and F). The results also showed an interaction effect be-
tween IUGR and Ado in the relative fluorescence density of
ADORA2A (P<0.01).
3.5. Protein levels of placental angiogenesis and adenosine
receptors
Fig. 5 displays the protein levels of angiogenesis-related markers
and adenosine receptors estimated by Western blotting. The results
showed that the expression of the angiogenesis-related signaling
pathway proteins p-Stat3 and p-Akt were decreased in the IUGR
placenta (P<0.05). Only ADORA2A had a lower protein level in the
IUGR placenta (P<0.05). Moreover, adenosine treatment notably
increased the protein expression levels of VCAM-1 (P<0.01), VEGF-
A(P<0.05) and Ang (P<0.01). Similar results were also observed
Fig. 1. Effects of maternal adenosine supplementation on the characteristics of piglets. (A) Piglet mean body weight (BW) at birth. (B) Placental efficiency ¼piglet weight (g)/
placental weight (g). Data were analyzed by unpaired Student's t-test. (C) Intrauterine growth restriction (IUGR) rate was analyzed using the Chi-square test. The number of sows
was 44 in each group. All data are presented as mean ±SEM.
**
P<0.01,
***
P<0.001.
Z. Wu, J. Nie, D. Wu et al. Animal Nutrition 13 (2023) 282e288
284
in the protein expression of p-Stat3 and p-Akt (P<0.01). Adenosine
treatment also increased the protein expression of ADORA2A
(P<0.01) and ADORA3 (P<0.05). An interaction effect was
observed in p-Stat3 and p-Akt protein expression between IUGR
and Ado (P<0.01), as well as a trend in interaction effect on the
protein level of VCAM1 (P¼0.09) and ADORA2A (P¼0.06).
Fig. 3. Real-Time PCR mRNA expression analysis of angiogenesis-related factors in placenta. (A) VEGF -A, (B) EGF, (C) Ang, (D) HIF-1
a
, (E) bFGF, (F) TGF-1
b
, (G) PDGF-A.n¼6. Statistical
significance was determined by 2 2 factorial treatment arrangement; factor 1 ¼IUGR; factor 2 ¼Ado; interaction between factor 1 and 2 ¼IUGR Ado. All data are presented as
mean ±SEM. The statistical significance in (A) and (C) were also determined by unpaired Student's t-test.
*
P<0.05, IUGR þCon vs. Normal þCon. IUGR ¼intrauterine growth
restriction; Ado ¼adenosine group; VEGF-A ¼vascular endothelial growth factor A; Ang ¼angiogenin.
Fig. 2. Effects of maternal adenosine supplementation on the vascular density of placenta. (A, B) The H&E method was used to detect blood vessel density in the placenta, and the
black arrows point to the placental blood vessels (bar ¼250
m
m, n¼6). (C, D) VCAM1 immunofluorescence staining in the placenta. (bar ¼50
m
m, n¼6). Statistical significance was
determined by 2 2 factorial treatment arrangement, factor 1 ¼IUGR, factor 2 ¼Ado, interaction between factor 1 and 2 ¼IUGR Ado. All data are presented as mean ±SEM.
IUGR ¼intrauterine growth restriction; Ado ¼adenosine group; VCAM1 ¼vascular cell adhesion molecule-1.
Z. Wu, J. Nie, D. Wu et al. Animal Nutrition 13 (2023) 282e288
285
4. Discussion
Previous studies have widely reported that abnormal placental
angiogenesis is associated with IUGR occurrence (Hu et al., 2020;
Tan et al., 2022), suggesting that improving the placental angio-
genesis might alleviate adverse pregnancy outcomes (Huang et al.,
2021a,2021b). Despite previous reports about the potential of
adenosine in promoting angiogenesis, the role of adenosine in
placental angiogenesis remains unclear. Pigs, as animals commonly
used in biomedical research on human pregnancy, have been
favored due to the physiological similarities they have to humans
(Bazer et al., 2012;Cai et al., 2018). In this study, we investigated
whether maternal adenosine supplementation during pregnancy
could improve pregnancy outcomes by detecting changes in
placental angiogenesis. Our results demonstrated that adenosine
supplementation could significantly increase the mean birth
weight and placental efficiency in piglets, and the Ado group was
shown to have a significantly lower IUGR rate than the Con group
(6.84% vs 12.47%), suggesting the great potential of adenosine
supplementation to ameliorate pregnancy outcomes in sows.
The placenta plays an important role in fetal growth (Reynolds
et al., 2006;Zhao et al., 2020), and adequate placental angiogen-
esis is essential for successful pregnancy and optimal growth of the
fetus (Gualdoni et al., 2021). Thus, to further explore the different
effects of adenosine on Normal and IUGR fetuses, the placentae
from IUGR and normal-weight (Normal) fetuses were separately
collected as 2 groups for further analysis. The results showed that
the IUGR placenta had significantly poorer angiogenesis, and
adenosine treatment could significantly promote angiogenesis in
the placenta (especially in the IUGR placenta), as well as restore the
low expression of VEGF-A and Ang in the IUGR placenta. Notably,
there was an interaction effect between IUGR and Ado in the pro-
angiogenesis effect of adenosine, and adenosine had no signifi-
cant effect on the mRNA expressions of angiogenesis-related genes
in the Normal placenta, suggesting that the beneficial effects of
adenosine treatment on IUGR occurrence may be attributed to the
presence of poor angiogenesis in the IUGR placenta. These results
were consistent with several previous studies reporting that (1)
IUGR piglets had lower vessel density in the placenta compared to
normal piglets, coupled with lower CD31 and VEGF-A level
(Campos et al., 2012;Hu et al., 2020;Wang et al., 2017); (2) there
was a close relationship between adenosine and embryonic
development (Rivkees and Wendler, 2017); (3) adenosine signaling
can be activated to exert biological effects, including but not limited
to angiogenesis, by up-regulating the expression of angiogenesis
factors such as VEGF, TGF-1
b
and Ang (Bahreyni et al., 2018;Gorain
et al., 2019;Zhang et al., 2019).
Differential binding to adenosine receptors may be critical for
adenosine activity and its biological effects (Salsoso et al., 2017). In
this study, the mRNA level of 4 adenosine receptors in the placenta
was further evaluated. Interestingly, only the expression of
ADORA2A showed a significant increase under adenosine treat-
ment both in the Normal and IUGR placenta. Although the mRNA
level of ADORA2B trended toward a similar expression with
ADORA2A, the changes in ADORA2B (up-regulated only 20% after
adenosine treatment) were much less than ADORA2A (up-regulated
nearly 50% after adenosine treatment). Further, immunostaining
analysis also showed that the expression of ADORA2A was simul-
taneously affected by IUGR and Ado, as well as their interaction
effects. These results seemed to imply that adenosine was more
Fig. 4. The expression of adenosine receptors in the placenta. (AeD) Real-Time PCR mRNA expression analysis of the adenosine receptors in the placenta (n¼6). (EeF) ADORA2A
immunofluorescence staining in the placenta (bar ¼50
m
m, n¼6). Statistical significance was determined by 2 2 factorial treatment arrangement; factor 1 ¼IUGR; factor
2¼Ado; interaction between factor 1 and 2 ¼IUGR Ado. All data are presented as mean ±SEM. IUGR ¼intrauterine growth restriction; Ado ¼adenosine group.
Z. Wu, J. Nie, D. Wu et al. Animal Nutrition 13 (2023) 282e288
286
likely to increase ADORA2A level to promote angiogenesis in the
IUGR placenta. The promoting effect of ADORA2A on angiogenesis
has been demonstrated in previous studies (Acurio et al., 2017;Liu
et al., 2017). Collectively, adenosine supplementation can up-
regulate ADORA2A level and improve angiogenesis in the IUGR
placenta.
Furthermore, the protein expression of angiogenesis-related
markers and adenosine receptors, as well as the possible underly-
ing mechanisms were explored. Only ADORA2A was found to have
the same expression trend as its mRNA expression (which
ADORA2B did not have), which further suggested the important
role ADORA2A plays in placental angiogenesis promoted by
adenosine. Similar results were also observed in angiogenesis-
related protein expression. Interestingly, the angiogenesis-related
signaling pathway Stat3 and Akt showed a similar expression
trend with angiogenesis markers. Previous studies also reported
that Stat3 is an important regulator in angiogenesis (Pereira et al.,
2015), and our previous study also demonstrated the ability of
Stat3 in improving placental angiogenesis (Hu et al., 2021;Huang
et al., 2021a). As the downstream signaling target of adenosine,
Akt also plays an important role in angiogenesis as previously re-
ported (Azambuja et al., 2019;Liu et al., 2017).
Fig. 5. Western blot protein expression analysis of angiogenesis-related factors (B, VCAM1; C, p-Stat3; D, p-Akt; E, VEGF-A; J, Ang) and adenosine receptors (F, ADORA3; G,
ADORA2B; H, ADORA2A; I, ADORA1) in the placenta. n¼6. Statistical significance was determined by 2 2 factorial treatment arrangement; factor 1 ¼IUGR; factor 2 ¼Ado;
interaction between factor 1 and 2 ¼IUGR Ado. All data are presented as mean ±SEM. IUGR ¼intrauterine growth restriction; Ado ¼adenosine group.
Z. Wu, J. Nie, D. Wu et al. Animal Nutrition 13 (2023) 282e288
287
5. Conclusions
Impaired angiogenesis in the placenta during pregnancy was
shown to be associated with the occurrence of IUGR piglets, while
maternal adenosine supply of 1 g/kg during the gestation of sows
could promote angiogenesis in placentae (especially in IUGR
placentae), finally increase the piglet birth weight and reduce the
IUGR rate. The underlying mechanism for the positive effects of
adenosine might be linked to the activation of ADORA2A and Stat3/
Akt signaling.
Author contributions
Chengquan Tan: Conceptualization, Methodology, Writing -
Review &Editing, Project administration. Hefeng Luo: Methodol-
ogy, Investigation, Writing - Original Draft. Zifang Wu: Investiga-
tion, Data Curation, Writing - Original Draft. Jiawei Nie:
Investigation, Data Curation. Deyuan Wu: Investigation. Shuangbo
Huang: Investigation. Jianzhao Chen: Investigation. Huangjin
Liang: Resources. Xiangyu Hao: Resources. Li Feng: Resources.
Declaration of competing interest
We declare that we have no financial and personal relationships
with other people or organizations that can inappropriately influ-
ence our work, and there is no professional or other personal in-
terest of any nature or kind in any product, service and/or company
that could be construed as influencing the content of this paper.
Acknowledgements
The present work was jointly supported by the National Key
R&D Program of China (2021YFD1300401) and Natural Science
Foundation of Guangdong Province (2021A1515012116).
Appendix supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.aninu.2023.02.003.
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