Hypertension in an Animal Model of HELLP Syndrome is Associated With Activation of Endothelin 1. (January 2016)

• Record Type: Journal Article
• Authors: Morris, Rachael; Spencer, Shauna-Kay; Kyle, Patrick B.; Williams, Jan Michael; Harris, Al'shondra; Owens, Michelle Y.; Wallace, Kedra
• Is Part Of: Reproductive sciences. Volume 23:Number 1(2016:Jan.)
• Page Start: 42
• Page End: 50
• Publication Date: 2016-01
• Subjects: endothelin -- hypertension -- HELLP syndrome -- hemolysis -- platelets; Reproductive health -- Periodicals; Reproduction -- Periodicals; 612.6
• DOI: 10.1177/1933719115592707
• Languages: English
• ISSNs: 1933-7191

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.