title: Hypoxia, AMPK activation and uterine artery vasoreactivity.
abstract: 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.
authors.affiliation: Centre for Trophoblast Research, Department of Physiology Development & Neuroscience, University of Cambridge, Cambridge, UK.
authors.forename: K L
authors.initials: KL
authors.lastname: Skeffington
authors.affiliation: Centre for Trophoblast Research, Department of Physiology Development & Neuroscience, University of Cambridge, Cambridge, UK.
authors.forename: J S
authors.initials: JS
authors.lastname: Higgins
authors.affiliation: Centre for Integrative Physiology, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: A D
authors.initials: AD
authors.lastname: Mahmoud
authors.affiliation: Centre for Integrative Physiology, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Evans
authors.affiliation: Centre for Trophoblast Research, Department of Physiology Development & Neuroscience, University of Cambridge, Cambridge, UK.
authors.forename: A N
authors.initials: AN
authors.lastname: Sferruzzi-Perri
authors.affiliation: Centre for Trophoblast Research, Department of Physiology Development & Neuroscience, University of Cambridge, Cambridge, UK.
authors.forename: A L
authors.initials: AL
authors.lastname: Fowden
authors.affiliation: Centre for Trophoblast Research, Department of Physiology Development & Neuroscience, University of Cambridge, Cambridge, UK.
authors.forename: H W
authors.initials: HW
authors.lastname: Yung
authors.affiliation: Centre for Trophoblast Research, Department of Physiology Development & Neuroscience, University of Cambridge, Cambridge, UK.
authors.forename: G J
authors.initials: GJ
authors.lastname: Burton
authors.affiliation: Centre for Trophoblast Research, Department of Physiology Development & Neuroscience, University of Cambridge, Cambridge, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: Giussani
authors.affiliation: Division of Basic Reproductive Sciences, Department of Obstetrics & Gynaecology, University of Colorado Denver, Aurora, CO, USA.
authors.forename: L G
authors.initials: LG
authors.lastname: Moore
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005260:Female; D005311:Fetal Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D055988:Uterine Artery / Q000378:metabolism / Q000503:physiopathology*; D014661:Vasoconstriction
chemical_list: D052250:Nitric Oxide Synthase Type III; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases