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dc.contributor.authorSkeffington, KLen
dc.contributor.authorHiggins, JSen
dc.contributor.authorMahmoud, ADen
dc.contributor.authorEvans, AMen
dc.contributor.authorSferruzzi-Perri, Amandaen
dc.contributor.authorFowden, Abigailen
dc.contributor.authorYung, Billyen
dc.contributor.authorBurton, Grahamen
dc.contributor.authorGiussani, Dinoen
dc.contributor.authorMoore, LGen
dc.date.accessioned2015-10-28T16:44:22Z
dc.date.available2015-10-28T16:44:22Z
dc.date.issued2015-06-25en
dc.identifier.citationSkeffington et al. The Journal of Physiology (2015) Vol. 594, pp. 1357-1369. doi: 10.1113/JP270995en
dc.identifier.issn0022-3751
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/252455
dc.description.abstractGenes 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.
dc.description.sponsorshipFunding for these studies was provided by the Wellcome Trust (084804/2/08/Z) to G.J.B., the British Heart Foundation and the Wellcome Trust to D.A.G., the Biotechnology and Biological Sciences Research Council (BBSRC) to A.L.F., a UK Wellcome Trust Programme Grant (WT081195MA) to A.M.E. and A.D.M., a BBSRC studentship and in vivo skills award to J.S.H., a National Health Medical Research Council and Centre for Trophoblast Research fellowship to A.N.S.-P., and a NIH RO1 grant (HLBI-079647) to L.G.M. along with sabbatical support from Wake Forest University.
dc.languageEnglishen
dc.language.isoenen
dc.publisherWiley
dc.titleHypoxia, AMPK activation and uterine artery vasoreactivityen
dc.title.alternativeAMPK and uterine artery vasodilationen
dc.typeArticle
dc.description.versionThis is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1113/JP270995en
prism.endingPage1369
prism.publicationDate2015en
prism.publicationNameThe Journal of Physiologyen
prism.startingPage1357
prism.volume594en
dc.rioxxterms.funderBBSRC
dc.rioxxterms.funderBHF
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.funderNIH
dc.rioxxterms.projectid084804/2/08/Z
dc.rioxxterms.projectidHLBI-079647
dcterms.dateAccepted2015-06-21en
rioxxterms.versionofrecord10.1113/JP270995en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-06-25en
dc.contributor.orcidSferruzzi-Perri, Amanda [0000-0002-4931-4233]
dc.contributor.orcidFowden, Abigail [0000-0002-3384-4467]
dc.contributor.orcidYung, Billy [0000-0002-0869-7426]
dc.contributor.orcidBurton, Graham [0000-0001-8677-4143]
dc.contributor.orcidGiussani, Dino [0000-0002-1308-1204]
dc.identifier.eissn1469-7793
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idBritish Heart Foundation (PG/14/5/30547)
pubs.funder-project-idBBSRC (BB/E002668/1)
pubs.funder-project-idWellcome Trust (084804/Z/08/Z)
rioxxterms.freetoread.startdate2016-07-31


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