title: Hypertension in an Animal Model of HELLP Syndrome is Associated With Activation of Endothelin 1.
abstract: Women with hypertensive forms of pregnancy such as hemolysis-elevated liver enzymes-low platelet syndrome have increased circulating endothelin 1; however, the relationship between hypertension and endothelin 1 has not been studied. Using an animal model, we sought to determine whether there was an increased activation/dysfunction of endothelin 1, the effect of endothelin 1 receptor-A blockade on hypertension and other manifestations of hemolysis, elevated liver enzymes, and low platelets syndrome. On gestational day 12, timed-pregnant rats were infused with soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEndoglin; 4.7 and 7 µg/kg) via mini-osmotic pumps for 8 days. A subset of rats were treated with receptor-A antagonist (ABT-627, 5mg/kg) for 8 days. Rats with hemolysis-elevated liver enzymes-low platelet syndrome had significantly increased hypertension (P = .0001), circulating endothelin 1 (P = .03), and a significant 3.3- and 7.2-fold increase in preproendothelin messenger RNA (mRNA) expression in the placenta and liver (P = .01 and .04). Urinary protein:creatinine ratio was significantly increased in these animals (P = .0007), and circulating factors from these rats stimulated a significant increase in endothelial cell secretion of endothelin 1 (P = .001) in an in vitro assay. Blockade of the endothelin 1 receptor A significantly decreased hypertension (P = .001), circulating endothelin 1, and interleukin 17 (P = .004 and .003), placental preproendothelin mRNA expression (P = .016), and urinary protein:creatinine ratio (P = .007) in rats with hemolysis-elevated liver enzymes-low platelet syndrome. Blockade of the endothelin 1 receptor A significantly decreased hemolysis (P = .009), liver enzymes (P = .011), and significantly increased platelet levels (P = .03) and decreased circulating CD4+ and CD8+ T lymphocytes (P = .0004 and .0001) in rats infused with sFlt-1 and sEndoglin. These data support the hypothesis that endothelin 1 activation has a critical role in pathophysiology of as hemolysis-elevated liver enzymes-low platelet syndrome.
authors.affiliation: Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Morris
authors.affiliation: Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Shauna-Kay
authors.initials: SK
authors.lastname: Spencer
authors.affiliation: Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Patrick B
authors.initials: PB
authors.lastname: Kyle
authors.affiliation: Department of Pharmacology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Jan Michael
authors.initials: JM
authors.lastname: Williams
authors.affiliation: Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Al'shondra
authors.initials: A
authors.lastname: Harris
authors.affiliation: Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Michelle Y
authors.initials: MY
authors.lastname: Owens
authors.affiliation: Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS, USA kwallace2@umc.edu.
authors.forename: Kedra
authors.initials: K
authors.lastname: Wallace
mesh_terms: D000818:Animals; D000077868:Atrasentan; D004195:Disease Models, Animal; D000071063:Endoglin; D019332:Endothelin-1 / Q000097:blood / Q000378:metabolism*; D005260:Female; D017359:HELLP Syndrome / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D006973:Hypertension / Q000097:blood* / Q000503:physiopathology; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000494:pharmacology
chemical_list: D000071063:Endoglin; D019332:Endothelin-1; D011759:Pyrrolidines; D040281:Vascular Endothelial Growth Factor Receptor-1; D000077868:Atrasentan
keywords: HELLP syndrome; endothelin; hemolysis; hypertension; platelets