Hypertension in an Animal Model of HELLP Syndrome is Associated With Activation of Endothelin 1

Rachael Morris; Shauna-Kay Spencer; Patrick B Kyle; Jan Michael Williams; Al'shondra Harris; Michelle Y Owens; Kedra Wallace

doi:10.1177/1933719115592707

Hypertension in an Animal Model of HELLP Syndrome is Associated With Activation of Endothelin 1

Reprod Sci. 2016 Jan;23(1):42-50. doi: 10.1177/1933719115592707. Epub 2015 Jun 30.

Authors

Rachael Morris¹, Shauna-Kay Spencer¹, Patrick B Kyle², Jan Michael Williams³, Al'shondra Harris¹, Michelle Y Owens¹, Kedra Wallace⁴

Affiliations

¹ Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS, USA.
² Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA.
³ Department of Pharmacology, University of Mississippi Medical Center, Jackson, MS, USA.
⁴ Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS, USA kwallace2@umc.edu.

PMID: 26130680
DOI: 10.1177/1933719115592707

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.

Keywords: HELLP syndrome; endothelin; hemolysis; hypertension; platelets.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Atrasentan
Disease Models, Animal
Endoglin
Endothelin-1 / blood
Endothelin-1 / metabolism*
Female
HELLP Syndrome / blood
HELLP Syndrome / metabolism*
HELLP Syndrome / physiopathology
Hypertension / blood*
Hypertension / physiopathology
Placenta / metabolism
Pregnancy
Pyrrolidines / pharmacology
Rats
Vascular Endothelial Growth Factor Receptor-1 / pharmacology

Substances

Endoglin
Endothelin-1
Pyrrolidines
Vascular Endothelial Growth Factor Receptor-1
Atrasentan