title: Progesterone blunts vascular endothelial cell secretion of endothelin-1 in response to placental ischemia.
abstract: OBJECTIVE
  Preeclampsia (PE) is associated with hypertension and elevated endothelin (ET-1), an indicator of endothelial cell activation and dysfunction. Reduction of uteroplacental perfusion (RUPP) in the pregnant rat model of PE is characterized by elevated mean arterial pressure, inflammatory cytokines, and activation of the ET-1 system. We aim to determine whether 17-alpha-hydroxyprogesterone caproate (17-OHPC) or progesterone suppresses these pathways.
  
  
  METHODS
  Plasma progesterone was purified from normal pregnant (NP) and PE patients and measured via enzyme-linked immunosorbent assay. Human umbilical vein endothelial cells were exposed to the sera with or without progesterone added and ET-1 was measured. Pregnant rats underwent the RUPP procedure with or without intraperitoneal 17-OHPC. Mean arterial pressure was compared in RUPP vs NP rats. Human umbilical vein endothelial cells were exposed to NP or RUPP sera, with and without progesterone and ET-1 measured.
  
  
  RESULTS
  Progesterone was significantly decreased in PE women compared with NP women. In response to human sera, ET-1 was elevated in PE women compared to NP women, and decreased with addition of progesterone. Mean arterial pressure was significantly elevated in RUPP vs NP rats but was attenuated by 17-OHPC. ET-1 secretion was stimulated significantly by RUPP compared to NP rat sera, but attenuated by progesterone.
  
  
  CONCLUSIONS
  Circulating progesterone is significantly lower in PE women compared to controls. 17-OHPC attenuates hypertension in response to placental ischemia in RUPP rats. Progesterone blunts vascular ET-1 stimulated at cellular level by sera from PE women or RUPP rats. Decreased circulating progesterone is associated with stimulation of ET-1. 17-OHPC supplementation blunts hypertension and progesterone blunts endothelial cell ET-1 secretion in response to placental ischemia.
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS. Electronic address: lkiprono@umc.edu.
authors.forename: Luissa V
authors.initials: LV
authors.lastname: Kiprono
authors.forename: Kedra
authors.initials: K
authors.lastname: Wallace
authors.forename: Janae
authors.initials: J
authors.lastname: Moseley
authors.forename: James
authors.initials: J
authors.lastname: Martin
authors.forename: Babbette
authors.initials: B
authors.lastname: Lamarca
mesh_terms: D000077713:17 alpha-Hydroxyprogesterone Caproate; D000818:Animals; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D006908:Hydroxyprogesterones / Q000494:pharmacology / Q000627:therapeutic use*; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology; D010920:Placenta; D021041:Placental Circulation / Q000502:physiology*; D011225:Pre-Eclampsia / Q000188:drug therapy / Q000378:metabolism*; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology / Q000627:therapeutic use*; D011372:Progestins / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019332:Endothelin-1; D006908:Hydroxyprogesterones; D011372:Progestins; D000077713:17 alpha-Hydroxyprogesterone Caproate; D011374:Progesterone
keywords: endothelin; placental ischemia; preeclampsia; progesterone
references.citation: J Matern Fetal Neonatal Med. 2006 Dec;19(12):763-72
references.pmid: 17190686
references.citation: Am J Obstet Gynecol. 2009 Sep;201(3):324.e1-6
references.pmid: 19733289
references.citation: Acta Obstet Gynecol Scand. 1975;54(3):195-202
references.pmid: 1163210
references.citation: Am J Hypertens. 2009 Oct;22(10):1120-5
references.pmid: 19745821
references.citation: Am J Perinatol. 2001;18(2):73-7
references.pmid: 11383703
references.citation: J Obstet Gynaecol Res. 2011 Oct;37(10):1342-5
references.pmid: 21564406
references.citation: Am J Reprod Immunol. 1997 Mar;37(3):240-9
references.pmid: 9127646
references.citation: Hypertension. 2008 Apr;51(4):1002-9
references.pmid: 18259010
references.citation: Hypertension. 2005 Oct;46(4):1022-5
references.pmid: 16144982
references.citation: Am J Obstet Gynecol. 2012 May;206(5):376-86
references.pmid: 22542113
references.citation: Acta Obstet Gynecol Scand. 2009;88(6):639-46
references.pmid: 19412798
references.citation: J Clin Endocrinol Metab. 2001 Jun;86(6):2505-12
references.pmid: 11397847
references.citation: Hypertension. 2005 Jul;46(1):82-6
references.pmid: 15928030
references.citation: Hypertension. 2001 Sep;38(3 Pt 2):718-22
references.pmid: 11566964
references.citation: Reprod Toxicol. 2012 Jan;33(1):15-9
references.pmid: 22120850
references.citation: Cancer Epidemiol Biomarkers Prev. 2003 Jul;12(7):647-50
references.pmid: 12869405
references.citation: Lancet. 1960 Jan 23;1(7117):198-9
references.pmid: 13813863
references.citation: Hypertension. 2001 Feb;37(2 Pt 2):485-9
references.pmid: 11230323
references.citation: Biol Reprod. 2012 Aug 23;87(2):36
references.pmid: 22649072
references.citation: Cochrane Database Syst Rev. 2006 Oct 18;(4):CD006175
references.pmid: 17054277
references.citation: Hypertension. 2003 Mar;41(3):437-45
references.pmid: 12623940
references.citation: Reprod Sci. 2010 Jun;17(6):532-9
references.pmid: 20360593
references.citation: Wien Klin Wochenschr. 2000 Apr 21;112(8):362-4
references.pmid: 10849942
references.citation: Hypertension. 2006 Mar;47(3):615-8
references.pmid: 16391174