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      Peroxisome proliferator-activated receptor gamma blunts endothelin-1-mediated contraction of the uterine artery in a murine model of high-altitude pregnancy

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          Abstract

          The environmental hypoxia of high altitude (HA) increases the incidence of intrauterine growth restriction (IUGR) approximately threefold. The peroxisome proliferator-activated receptor γ (PPAR-γ), a ligand-activated nuclear receptor that promotes vasorelaxation by increasing nitric oxide and downregulating endothelin-1 (ET-1) production, has been implicated in IUGR. Based on our prior work indicating that pharmacologic activation of the PPARγ pathway protects against hypoxia-associated IUGR, we used an experimental murine model to determine whether such effects may be attributed to vasodilatory effects in the uteroplacental circulation. Using wire myography, ex vivo vasoreactivity studies were conducted in uterine arteries (UtA) isolated from pregnant mice exposed to hypoxia or normoxia from gestational day 14.5 to 18.5. Exposure to troglitazone, a high-affinity PPARγ agonist, induced vasorelaxation in UtA pre-constricted with phenylephrine, with HA-UtA showing increased sensitivity. Troglitazone blunted ET-1-induced contraction of UtA in hypoxic and normoxic dams equivalently. Immunohistological analysis revealed enhanced staining for ET-1 receptors in the placental labyrinthine zone in hypoxic compared to normoxic dams. Our results suggest that pharmacologic PPAR-γ activation, via its vasoactive properties, may protect fetal growth under hypoxic conditions by improving uteroplacental perfusion and thereby justify further investigation into PPARγ as a therapeutic target for IUGR in pregnancies complicated by hypoxia.

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          Author and article information

          Journal
          8804484
          3815
          FASEB J
          FASEB J.
          FASEB journal : official publication of the Federation of American Societies for Experimental Biology
          0892-6638
          1530-6860
          25 February 2020
          23 January 2020
          March 2020
          01 March 2021
          : 34
          : 3
          : 4283-4292
          Affiliations
          [1 ]Integrated Physiology Program, University of Colorado Graduate School, Aurora, CO, USA.
          [2 ]Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, CO, USA.
          [3 ]Department of Biochemistry, Colorado Mesa University, Grand Junction, CO, USA
          [4 ]Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
          Author notes

          AUTHOR CONTRIBUTIONS

          S. Lane and C. Julian designed research; S. Lane analyzed data; S. Lane, A. Doyle, E. Bales and J. Houck performed research; L. Moore and R. Lorca reviewed and contributed to the paper; S. Lane and C. Julian wrote the paper.

          Corresponding Author: Colleen G. Julian, PhD, Department of Medicine, University of Colorado Denver, 12700 E 19 th Avenue, Mailstop 8611, 3 rd Floor Research Complex 2, P15-3122, Aurora, CO 80045, colleen.julian@ 123456ucdenver.edu , Phone: 303-724-6443, Fax: 303-724-1799
          Article
          PMC7060097 PMC7060097 7060097 nihpa1069050
          10.1096/fj.201902264RR
          7060097
          31970838
          2ba9b220-7c25-4435-aeed-5f10e462fe44
          History
          Categories
          Article

          thiazolidinedione,hypoxia,vascular function,intrauterine growth restriction

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