Hypoxia, AMPK activation and uterine artery vasoreactivity
Open accessAbstract
Key points: Uterine artery vasodilatation is a key mechanism for increasing utero‐placental blood flow and fetal nutrient supply. Since the pioneering work of Joseph Barcroft, the natural laboratory of high altitude has been used to study the mechanisms regulating uterine artery blood supply and fetal growth. Genes near the metabolic sensor adenosine monophosphate‐activated protein kinase (AMPK) have been implicated in genetic protection from high altitude‐associated fetal growth restriction. We show that AMPK is present in utero‐placental tissues and has vasodilator effects in murine uterine arteries, and that exposure to chronic hypoxia sufficient to decrease fetal growth increases the vasodilator actions of AMPK in opposing phenylephrine‐induced vasoconstriction. These results point to AMPK as being a key link between maternal vascular responses to pregnancy and fetal growth. Manipulation of AMPK may be a novel mechanism for developing new therapies in pregnancies complicated by chronic hypoxia. Genes near adenosine monophosphate‐activated protein kinase‐α1 ( PRKAA1 ) have been implicated in the greater uterine artery (UtA) blood flow and relative protection from fetal growth restriction seen in altitude‐adapted Andean populations. Adenosine monophosphate‐activated protein kinase (AMPK) activation vasodilates multiple vessels but whether AMPK is present in UtA or placental tissue and influences UtA vasoreactivity during normal or hypoxic pregnancy remains unknown. We studied isolated UtA and placenta from near‐term C57BL/6J mice housed in normoxia ( n = 8) or hypoxia (10% oxygen, n = 7–9) from day 14 to day 19, and placentas from non‐labouring sea level ( n = 3) or 3100 m ( n = 3) women. Hypoxia increased AMPK immunostaining in near‐term murine UtA and placental tissue. RT‐PCR products for AMPK‐α1 and ‐α2 isoforms and liver kinase B1 (LKB1; the upstream kinase activating AMPK) were present in murine and human placenta, and hypoxia increased LKB1 and AMPK‐α1 and ‐α2 expression in the high‐ compared with low‐altitude human placentas. Pharmacological AMPK activation by A769662 caused phenylephrine pre‐constricted UtA from normoxic or hypoxic pregnant mice to dilate and this dilatation was partially reversed by the NOS inhibitor l ‐NAME. Hypoxic pregnancy sufficient to restrict fetal growth markedly augmented the UtA vasodilator effect of AMPK activation in opposition to PE constriction as the result of both NO‐dependent and NO‐independent mechanisms. We conclude that AMPK is activated during hypoxic pregnancy and that AMPK activation vasodilates the UtA, especially in hypoxic pregnancy. AMPK activation may be playing an adaptive role by limiting cellular energy depletion and helping to maintain utero‐placental blood flow in hypoxic pregnancy.
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“In vivo study revealed that activated AMPK increased uterine artery blood flow velocity either by inhibition of vasoconstriction prostanoids or by increasing nitric oxide production [12].”
BackgroundIntermittent hypoxia impairs uterine artery function in pregnant mice
Badran, M., Abuyassin, B., Ayas, N., & Laher, I. (2019) · The Journal of Physiology · doi:10.1113/jp277775 · Cited by 48 · see citing works
“2015) and also after exposure to sustained hypoxia (Skeffington et al. 2016).”
BackgroundRodent models in placental research. Implications for fetal origins of adult disease
Aguilera-Martínez, N., Salas‐Pérez, F., Ortíz, M., Álvarez, D., Echiburú, B., & Maliqueo, M. A. (2022) · Animal Reproduction · doi:10.1590/1984-3143-ar2021-0134 · Cited by 46 · see citing works
“In the same way, AMPK was activated in the uterine artery and the labyrinth zone in response to 10% hypoxia (Skeffington et al., 2016)”
MethodWesolowski, S. R., & Hay, W. W. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.12.016 · Cited by 42 · see citing works
“…have focused on placenta function and nutrient delivery and found decreased glucose transport and delivery to the fetus (Illsley et al., 2010, Skeffington et al., 2015, Zamudio et al., 2010), similar to the reduced glucose uptake found in the IUGR sheep fetus (Limesand et al., 2007, Thureen…”
BackgroundGuidelines for assessing maternal cardiovascular physiology during pregnancy and postpartum
Collins, H. E., Alexander, B. T., Care, A. S., Davenport, M. H., Davidge, S. T., Eghbali, M., Giussani, D. A., Hoes, M. F., Julian, C. G., LaVoie, H. A., et al. (2024) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00055.2024 · Cited by 42 · see citing works
Self-citationMaternal vascular responses to hypoxia in a rat model of intrauterine growth restriction
Aljunaidy, M. M., Morton, J. S., Cooke, C. M., & Davidge, S. T. (2016) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00119.2016 · Cited by 40 · see citing works
“Gestational hypoxia can also increase uterine artery vasodilator responses to AMPK through both nitric oxide (NO)-dependent and -independent mechanisms in pregnant mice (29).”
BackgroundHigh Altitude Reduces NO-Dependent Myometrial Artery Vasodilator Response During Pregnancy
Lorca, R. A., Lane, S. L., Bales, E. S., Nsier, H., Yi, H., Donnelly, M. A., Euser, A. G., Julian, C. G., & MOORE, L. G. (2019) · Hypertension · doi:10.1161/hypertensionaha.119.12641 · Cited by 40 · see citing works
Self-citationHansell, J. A., Richter, H. G., Camm, E. J., Herrera, E. A., Blanco, C. E., Villamor, E., Patey, O. V., Lock, M. C., Trafford, A. W., Galli, G. L. J., et al. (2021) · Journal of Pineal Research · doi:10.1111/jpi.12766 · Cited by 39 · see citing works
Self-citationPlacental hypoxia: What have we learnt from small animal models?
Siragher, E. J., & Sferruzzi-Perri, A. N. (2021) · Placenta · doi:10.1016/j.placenta.2021.03.018 · Cited by 34 · see citing works
Self-citationThe emerging role of AMPK in the regulation of breathing and oxygen supply
Evans, A. M., Mahmoud, A. D., Moral‐Sanz, J., & Hartmann, S. (2016) · Biochemical Journal · doi:10.1042/bcj20160002 · Cited by 33 · see citing works
Self-citationLane, S. L., Dodson, R. B., Doyle, A. S., Park, H., Rathi, H., Matarrazo, C. J., MOORE, L. G., Lorca, R. A., Wolfson, G. H., & Julian, C. G. (2019) · The FASEB Journal · doi:10.1096/fj.201900214r · Cited by 32 · see citing works
“OurHxmodel induced a 21% reduction of fetalweight, a magnitude of growth restriction similar to the 21–26% reduction seen with a near-term, 5-d normobaric hypoxia (10%O2) inmice (26).”
BackgroundSelf-citationLane, S. L., Houck, J. A., Doyle, A. S., Bales, E. S., Lorca, R. A., Julian, C. G., & MOORE, L. G. (2020) · The Journal of Physiology · doi:10.1113/jp279341 · Cited by 32 · see citing works
“Consistent with previous reports, hypoxia had no effect on the uterine artery contractile response to phenylephrine (Hu et al. 1996, 1999; Mateev et al. 2003; Skeffington et al. 2016), and AMPK activation with A769662 consistently blunted the phenylephrine response (Skeffington et al.”
BackgroundResultInfluentialSelf-citationHigh altitude regulates the expression of AMPK pathways in human placenta
Lorca, R. A., Houck, J. A., Laurent, L. C., Matarazzo, C. J., Baker, K., Horii, M., Nelson, K. K., Bales, E. S., Euser, A. G., Parast, M. M., et al. (2021) · Placenta · doi:10.1016/j.placenta.2021.01.010 · Cited by 32 · see citing works
Self-citationPascual‐Morena, C., Cavero‐Redondo, I., Álvarez‐Bueno, C., Lucerón‐Lucas‐Torres, M., Sanabria‐Martínez, G., Poyatos‐León, R., Rodríguez‐Martin, B., & Martínez‐Vizcaíno, V. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10163490 · Cited by 27 · see citing works
Hung, T., Wu, C., & Chen, S. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.788969 · Cited by 28 · see citing works
Salazar‐Petres, E., Pereira‐Carvalho, D., López‐Tello, J., & Sferruzzi-Perri, A. N. (2022) · Biology of Reproduction · doi:10.1093/biolre/ioac056 · Cited by 32 · see citing works
“Moreover, AMPK in the placenta has been linked to maternal vascular responses and changes in placental morphology and fetal growth in hypoxic pregnancy [8, 50].”
BackgroundSelf-citationLorca, R. A., Matarazzo, C. J., Bales, E. S., Houck, J. A., Orlicky, D. J., Euser, A. G., Julian, C. G., & MOORE, L. G. (2020) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00644.2019 · Cited by 27 · see citing works
Self-citationWaker, C. A., Albers, R. E., Pye, R. L., Doliboa, S. R., Wyatt, C. N., Brown, T. L., & Mayes, D. A. (2017) · Stem Cells and Development · doi:10.1089/scd.2016.0252 · Cited by 27 · see citing works
“In addition, AMPK is present in the placenta of humans and mice, is increased under hypoxia, and facilitates uterine artery blood flow [17].”
BackgroundHigh-altitude population neonatal and maternal phenotypes associated with birthweight protection
Dolma, P., Angchuk, P. T., Jain, V., Dadhwal, V., Kular, D., Williams, D. J., Montgomery, H., & Hillman, S. L. (2021) · Pediatric Research · doi:10.1038/s41390-021-01593-5 · Cited by 24 · see citing works
Mechanisms of Uterine Artery Dysfunction in Pregnancy Complications
Morton, J. S., Care, A. S., & Davidge, S. T. (2017) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000000468 · Cited by 27 · see citing works
Effects of hypoxia on uteroplacental and fetoplacental vascular function during pregnancy
Arenas, G. A., & Lorca, R. A. (2024) · Frontiers in Physiology · doi:10.3389/fphys.2024.1490154 · Cited by 23 · see citing works
Lane, S. L., Doyle, A. S., Bales, E. S., Lorca, R. A., Julian, C. G., & MOORE, L. G. (2019) · Biology of Reproduction · doi:10.1093/biolre/ioz208 · Cited by 23 · see citing works
Self-citationAssociation of placental nutrient sensing pathways with birth weight
Lazo-de-la-Vega-Monroy, M.-L., Mata-Tapia, K.-A., García-Santillán, J.-A., Corona-Figueroa, M.-A., Gónzalez-Domínguez, M.-I., Gomez-Zapata, H.-M., Malacara, J. M., Daza-Benítez, L., & Barbosa‐Sabanero, G. (2020) · Reproduction · doi:10.1530/rep-20-0186 · Cited by 20 · see citing works
Valenzuela-Melgarejo, F. J., Lagunas, C., Carmona-Pastén, F., Jara-Medina, K., & Delgado, G. V. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.767684 · Cited by 18 · see citing works
Hypoxia, fetal and neonatal physiology: 100 years on from Sir Joseph Barcroft
Giussani, D. A., Bennet, L., Sferruzzi-Perri, A. N., Vaughan, O. R., & Fowden, A. L. (2016) · The Journal of Physiology · doi:10.1113/jp272000 · Cited by 17 · see citing works
Self-citationWang, Z., Camm, E. J., Nuzzo, A. M., Spiroski, A., Skeffington, K. L., Ashmore, T. J., Rolfo, A., Todros, T., Logan, A., Ma, J., et al. (2024) · The Journal of Physiology · doi:10.1113/jp286178 · Cited by 16 · see citing works
“The contribution of NO independent mechanisms to the vascular relaxation induced by ACh was calculated by the AUC for ACh + l-NAME (Giussani et al., 2012; Skeffington et al., 2016).”
BackgroundMethodSelf-citationDing, Y., Xia, Y., Gu, W., & Lu, L. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.09.099 · Cited by 16 · see citing works
Finley, J. (2018) · Medical Hypotheses · doi:10.1016/j.mehy.2018.05.015 · Cited by 16 · see citing works
Placental Adaptation to Hypoxia: The Case of High-Altitude Pregnancies
Ahrens, S., & Singer, D. (2025) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph22020214 · Cited by 18 · see citing works
“The higher blood flow is also contributed to by greater AMP-dependent kinase (AMPK)-mediated vasodilation in women of HA ancestry [78].”
AMPK and Placental Progenitor Cells
Kaufman, M. R., & Brown, T. L. (2016) · Proceedings of the Fourth International Symposium on Polarization Phenomena in Nuclear Reactions · doi:10.1007/978-3-319-43589-3_4 · Cited by 14 · see citing works
Mundo, W., Wolfson, G. H., MOORE, L. G., Houck, J. A., Park, D., & Julian, C. G. (2021) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00520.2020 · Cited by 13 · see citing works
Self-citationMaternal serum AMP-activated protein kinase levels in mild and severe preeclampsia
Köroğlu, N., Tola, E. N., Yüksel, İ. T., Çetin, B. A., Turhan, U., Topcu, G., & Dağ, İ. (2018) · The Journal of Maternal-Fetal & Neonatal Medicine · doi:10.1080/14767058.2018.1448774 · Cited by 12 · see citing works
“of maternal uterine artery blood flow [16].”
MOORE, L. G., Lorca, R. A., Gumina, D. L., Wesolowski, S. R., Reisz, J. A., Cioffi‐Ragan, D., Houck, J. A., Banerji, S., Euser, A. G., D’Alessandro, A., et al. (2024) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00193.2024 · Cited by 11 · see citing works
Self-citationTan, B., Tong, C., Yuan, Y., Xu, P. A., Wen, L., Zhang, C., Zheng, Y., Lin, L. W., Zhu, F., Gui, S., et al. (2019) · Cellular Physiology and Biochemistry · doi:10.33594/000000023 · Cited by 11 · see citing works
In vivo noninvasive systemic myography of acute systemic vasoactivity in female pregnant mice
Huda, K., Lawrence, D. J., Thompson, W., Lindsey, S. H., & Bayer, C. L. (2023) · Nature Communications · doi:10.1038/s41467-023-42041-8 · Cited by 10 · see citing works
MacMillan, S., & Evans, A. M. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00655 · Cited by 9 · see citing works
“Accordingly, AMPK has also been implicated in the regulation of uterine artery reactivity during hypoxia (Skeffington et al., 2015), perhaps linking maternal metabolic and cardiovascular responses during pregnancy and governing oxygen and nutrient supply to the fetus.”
BackgroundSelf-citationDifferential placental CpG methylation is associated with chronic lung disease of prematurity
Jackson, W., Junior, H. P. D. O. S., Hartwell, H. J., Gower, W. A., Chhabra, D., Hagood, J. S., Laughon, M. M., Payton, A., Smeester, L., Roell, K. R., et al. (2021) · Pediatric Research · doi:10.1038/s41390-021-01868-x · Cited by 7 · see citing works
Melatonin modulates metabolic adaptation of pancreatic stellate cells subjected to hypoxia
Estarás, M., Martínez, R., Sánchez, A. G., Ortiz-Placín, C., Iovanna, J., Santofimia‐Castaño, P., & González, A. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115118 · Cited by 7 · see citing works
Placental structure, function and mitochondrial phenotype relate to fetal size and sex in micePreprint
Salazar‐Petres, E., Carvalho, D. P., López‐Tello, J., & Sferruzzi-Perri, A. N. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.07.22.453249 · Cited by 5 · see citing works
Self-citationCardiovascular outcome in 12‐month‐old male and female offspring of metformin‐treated obese mice
Schoonejans, J. M., Wilsmore, P., Mennitti, L. V., Wong, K. K., Ashmore, T. J., Garrud, T. A. C., Blackmore, H. L., Patey, O. V., Fernandez‐Twinn, D. S., Giussani, D. A., et al. (2025) · The Journal of Physiology · doi:10.1113/jp288696 · Cited by 3 · see citing works
Self-citationFetal growth and congenital heart disease at high altitude
Giussani, D. A. (2025) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2024.0177 · Cited by 5 · see citing works
“This is due, in part, to an increase in constrictor reactivity coupled with a decrease in dilator reactivity in uterine arteries when gestation occurs under chronic hypoxic conditions, as has been shown in humans, sheep, guinea pigs, rats and mice [19–29].”
Self-citationAdaptive PRKAA1 variant in Andeans is associated with improved ventilation and sleep phenotypes
Lawrence, E. S., Gu, W., Kong, M. C., Fassardi, S., Anza‐Ramirez, C., Moya, E. A., Heinrich, E. C., Yu, J. J., Orr, J. E., Cao, S., et al. (2025) · iScience · doi:10.1016/j.isci.2025.112911 · Cited by 3 · see citing works
Self-citationHigh-altitude pregnancy adaptation: evidence from a Himalayan population in Leh
Hillman, S. L., & Dolma, P. (2025) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2024.0396 · Cited by 3 · see citing works
“Animal studies of the mechanisms underpinning UtA vasodilation support a role for the metabolic sensor, AMPK, which was found to be present in placental tissue and influenced vasodilation in the presence of chronic hypoxia [31–33].”
AMPK function in uterine vasculature and placenta at high altitude
Lorca, R. A. (2025) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2024.0174 · Cited by 3 · see citing works
The uteroplacental circulation at high altitude: adaptation and maladaptation
Hu, X., Dasgupta, C., Gao, Y., Kremsky, I., Mata‐Greenwood, E., & Zhang, L. (2025) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2024.0179 · Cited by 3 · see citing works
MOORE, L. G., Wesolowski, S. R., Lorca, R. A., & Julian, C. G. (2025) · Acta Physiologica · doi:10.1111/apha.70093 · Cited by 2 · see citing works
Self-citationAwad, O., Malek, A., & Ogeng’o, J. A. (2017) · Anatomy Journal of Africa · doi:10.4314/aja.v6i1.150686 · Cited by 2 · see citing works
Fan, C., Chen, C., Liu, R., Maimaiti, M., Li, C., Zao, W., Lv, W., Xu, G., & Zhao, G. (2025) · Frontiers in Veterinary Science · doi:10.3389/fvets.2025.1659668 · Cited by 1 · see citing works
“Furthermore, AMPK activation promotes uterine artery vasodilation, suggesting that it helps maintain uterine placental blood flow and ensures normal pregnancy (50).”
El-Domiaty, H. F., Esa, W. A., & Allah, N. A. (2024) · Menoufia Medical Journal · doi:10.59204/2314-6788.1150
Shimada, H., Sakuragi, T., Zaegel, V., Kramer, A. W., Boyle, K. E., Powell, T. L., Jansson, T., & Rosario, F. J. (2026) · Antioxidants · doi:10.3390/antiox15080977
Arenas, G. A., Herrera, E. A., Krause, B. J., Giussani, D. A., Julian, C. G., MOORE, L. G., & Lorca, R. A. (2026) · Physiological Reviews · doi:10.1152/physrev.00003.2026
Self-citation
- Authors
- Skeffington, K. L., Higgins, J. S., Mahmoud, A. D., Evans, A. M., Sferruzzi‐Perri, A. N., Fowden, A. L., Yung, H. W., Burton, G. J., Giussani, D. A., & Moore, L. G.
- Affiliations
- University of Cambridge (GB)
- University of Edinburgh (GB)
- Centre for Trophoblast Research, Department of Physiology Development & Neuroscience University of Cambridge Cambridge UK
- University of Colorado Anschutz (US)
- Corresponding author
- Moore, L. G.
- ORCID
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2015-07-31
- Volume
- 594
- Issue
- 5
- Pages
- 1357-1369
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC4771787
- OpenAlex
- W1530409697
- Cited by
- 69
- References
- 65
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 5 · 2023: 1 · 2022: 5 · 2021: 10 · 2020: 5 · 2019: 8 · 2018: 5 · 2017: 8 · 2016: 8 · 2015: 3
- FWCI
- 9.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (publishedVersion, other-oa)
- Apollo (University of Cambridge) (acceptedVersion)
- Funders
- National Institutes of Health (079647)
- Wellcome Trust (084804/2/08/Z)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › High Altitude and Hypoxia
- Keywords
- AMPK, chronic hypoxia, fetal growth restriction, uteroplacental blood flow, high altitude, LKB1, A769662, phenylephrine vasoconstriction, placenta, pregnancy, AMPK isoforms, Andean peoples, fetal nutrient supply
- MeSH terms
- Animals, Female, Fetal Hypoxia, Mice, Inbred C57BL, Placenta, Pregnancy, Vasoconstriction, Protein Serine-Threonine Kinases, Mice, Nitric Oxide Synthase Type III, AMP-Activated Protein Kinases, Uterine Artery
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