Abstract 293: Endothelial Type B Endothelin Receptor is a Critical Microvascular Target in Placental Ischemia and Tumor Necrosis Factor-Mediated Hypertensive Pregnancy
Preeclampsia is a pregnancy-related hypertensive disorder (HTN-Preg) with unclear mechanism, and a role of cytokines and endothelin-1 (ET-1) has been suggested. We have recently shown downregulation of endothelial type B ET-1 receptor (ETBR) in Preg rats with reduced uterine perfusion pressure (RUPP). To test if cytokines are a possible mechanism linking RUPP to downregulation of ETBR, day 14-Preg rats were either nontreated or infused with TNFα (200 ng/kg/day), and RUPP rats were either nontreated or infused with the TNFα decoy receptor etanercept (0.4 mg/kg/day) for 5 days by osmotic minipump. On day 19, BP was recorded and mesenteric microvessels were isolated for simultaneous measurement of diameter and [Ca2+]i (fura-2 340/380 ratio). BP was in TNFα-Preg (127±8) > Preg (97±5mmHg) and in etanercept-RUPP (113±2) < RUPP (124±3mmHg). ET-1 vasoconstriction was in TNFα-Preg (86.1±4.7) > Preg (58.1±5.2%), and in etanercept-RUPP (65.9±5.0) < RUPP (86.2±3.7%). ET-1 caused parallel increases in microvascular [Ca2+]i that were in TNFα-Preg (0.90±0.01) > Preg (0.86±0.01), and in etanercept-RUPP (0.85±0.01) < RUPP (0.92±0.01). Endothelium removal or microvessel treatment with ETBR antagonist BQ-788 enhanced ET-1 vasoconstriction and [Ca2+]i in Preg and etanercept-RUPP, but not in TNFα-Preg or RUPP. ETBR-mediated relaxation with IRL-1620 was in TNFα-Preg (4.11±6.1) < Preg (28.8±4.2%), and in etanercept-RUPP (20.2±4.6) > RUPP (10.17±2.9%). The NOS inhibitor L-NAME partially reduced ACh-induced and ETBR-mediated relaxation in Preg and etanercept-RUPP, but not TNFα-Preg or RUPP, suggesting decreased NO-dependent and ETBR-mediated vasorelaxation in HTN-Preg. Addition of the K+ channel blocker teraethylammonium (non specific), or apamin (SKCa) plus TRAM-34 (IKCa) abolished the remaining ETBR-mediated relaxation in all groups, suggesting equal role of EDHF. Thus similar to RUPP, increasing TNFα in Preg rats increases ET-1 microvascular constriction and decreases ETBR-mediated NO-dependent vasodilation, and counteracting TNFα reduces BP and ET-1 vasoconstriction, and enhances ETBR-mediated vasodilation in RUPP rats. The results support that endothelial ETBR is a major microvascular target in placental ischemia and TNFα-mediated HTN-Preg.
Author Disclosures: M.Q. Mazzuca: None. K.M. Mata: None. R.A. Khalil: None.
This research has received full or partial funding support from the American Heart Association, Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).
- © 2014 by American Heart Association, Inc.