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.

Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia

“…It is possible that in severe PE and in HELLP syndrome the production of ET-1 is so augmented that ET-1 release “loses” its paracrine directionality and consequently an increase in circulating ET-1 levels is detected. This is supported by reports that rat models that mimic severe PE and HELPP syndrome have increased plasma ET-1 levels (Johnson et al, 2014; Morris et al, 2015) (Table 2). …”

“…sEng may act in concert with sFlt-1 to induce vascular permeability, proteinuria, IUGR and severe HTN in pregnant rats (Venkatesha et al, 2006). Pregnant rats infused with both sFlt-1 and sEng via mini-osmotic pump show HELLP syndrome-like features (Morris et al, 2015). Also, sEng impairs the formation of endothelial tubes in cultured HUVECs (Venkatesha et al, 2006).…”

Angiogenic imbalance and diminished matrix metalloproteinase-2 and -9 underlie regional decreases in uteroplacental vascularization and feto-placental growth in hypertensive pregnancy

“…The levels of sEng are higher in preeclampsia and the hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome compared with normal pregnant women [21, 88], and the serum and placenta levels of sEng are increased while serum TGF-β levels are decreased in RUPP rats [61]. When co-administered with sFlt-1 in pregnant rats, sEng induces vascular permeability, proteinuria, IUGR, severe HTN-Preg and HELLP syndrome-like features [89]. The expression of sEng is increased in placental explants exposed to hypoxia [90], and sEng impairs tube formation in human umbilical vein endothelial cells (HUVECs) [88].…”

Inhibition of T‐cell activation attenuates hypertension,TNFα,IL‐17, and blood–brain barrier permeability in pregnant rats with angiogenic imbalance

“…Infusion or overexpression of sFlt-1 and sEng into normal pregnant rats leads to a HELLP like phenotype in the recipient rats. This phenotype is expressed not only by the increase in hemolysis, elevated liver enzymes and decreased platelets, but also by a significant increase in mean arterial pressure, inflammatory cytokines, endothelin-1, CD4 + and CD8 + T lymphocytes 8–10 . A substantial number of studies have demonstrated that systemic inflammation mediated by inflammatory cytokines, anti-angiogenic growth factors, CD4 + T cells, or the damaged vascular endothelium can impair the BBB 11–13 .…”

“…However, CD8 + T cells are associated with neuroinflammatory conditions such as neurological paraneoplastic syndromes and multiple sclerosis 15, 16 . As CD4 + and CD8 + T cells are increased in response to infusion of sFlt-1 and sEng 9, 10 we sought to determine if 1) rats with HELLP syndrome had an increase in BBB permeability and 2) if T cells contributed to the inflammation and any potential increase in BBB permeability in an animal model of HELLP syndrome.…”