Downregulation of Microvascular Endothelial Type B Endothelin Receptor Is a Central Vascular Mechanism in Hypertensive Pregnancy

Abstract

Preeclampsia is a pregnancy-related disorder characterized by hypertension (HTN) with unclear mechanism. Studies have shown endothelial dysfunction and increased endothelin-1 (ET-1) levels in hypertensive-pregnancy (HTN-Preg). ET-1 activates endothelin receptor type-A (ETAR) in vascular smooth muscle to induce vasoconstriction, but the role of vasodilator endothelial ETBR in the changes in blood pressure (BP) and vascular function in HTN-Preg is unclear. To test if downregulation of endothelial ETBR expression/activity plays a role in HTN-Preg, BP was measured in Norm-Preg rats and rat model of HTN-Preg produced by reduction of uteroplacental perfusion pressure (RUPP), and mesenteric microvessels were isolated for measuring diameter, [Ca2+]i, and ETAR and ETBR levels. BP, ET-1 and KCI-induced vasoconstriction and [Ca2+]i were greater in RUPP than Norm-Preg rats. Endothelium-removal or microvessel treatment with ETBR antagonist BQ-788 enhanced ET-1 vasoconstriction and [Ca2+]i in Norm-Preg, but not RUPP, suggesting reduced vasodilator ETBR in HTN-Preg. ET-1+ETAR antagonist BQ-123, and ETBR agonists sarafotoxin 6c (S6c) and IRL-1620 caused less vasorelaxation and nitrate/nitrite production in RUPP than Norm-Preg. The NOS inhibitor L-NAME reduced S6c- and IRL-1620-induced relaxation in Norm-Preg but not RUPP, supporting that ETBR-mediated NO pathway is compromised in RUPP. RT-PCR, Western blots and immunohistochemistry revealed reduced endothelial ETBR expression in RUPP. Infusion of BQ-788 increased BP in Norm-Preg, and infusion of IRL-1620 reduced BP and ET-1 vasoconstriction and [Ca2+]i and enhanced ETBR-mediated vasorelaxation in RUPP. Thus downregulation of microvascular vasodilator ETBR is a central mechanism in HTN-Preg, and increasing ETBR activity could be a target in managing preeclampsia.

Maternal Vascular Physiology in Preeclampsia

“…Expression and activity of endothelial ET B receptors were reduced in rats with preeclampsia-like features (ie, hypertension, intrauterine growth restriction, proteinuria, renal dysfunction) induced by surgical reduction of uterine blood flow as compared with sham controls. 63 Others have shown that contractile responses to inactive precursor big ET-1 were increased in mesenteric arteries from this experimental model and that inhibition of matrix metalloproteinase, an enzyme that catalyzes the conversion of big ET-1 to ET-1, abolished the enhanced contractile responses. 65 Collectively, studies on endothelium-derived constrictors suggest that TxA 2 and ET-1 contribute to maternal vascular dysfunction in women with preeclampsia and in animal models with experimental preeclampsia.…”

“…63 Pharmacological inhibition of ET A reduces preeclampsia-like symptoms in various models of experimental preeclampsia, indicating that the ET-1 contribution to preeclampsia is ET A dependent. 64 ET B receptors are also involved in experimental preeclampsia.…”

Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy

“…6 and Table 1). DPN maximum relaxation and EC 50 were not different in all vessels of pregnant versus virgin rats. G1-induced maximum relaxation was only greater in the aorta of pregnant versus virgin rats (Fig.…”

“…We assessed if pregnancy-induced changes in vascular ERs could affect vascular function. In blood vessels isolated from virgin rats and precontracted with Phe, all ER agonists caused greater maximum relaxation with no difference in EC 50 in the mesenteric and renal artery versus the aorta and carotid artery (Fig. 6 and Table 1).…”

“…Rats were allowed to recover from anesthesia for at least 1 h. The carotid arterial catheter was connected to a pressure transducer attached to an amplifier and BP recorder (Living System Instrumentation, Burlington, VT). BP in conscious rats was recorded every 20 min for 1 h, and the average BP was measured (50).…”