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Soluble fms‐like tyrosine kinase‐1 (sFlt‐1) Links Placental Ischemia to Downregulation of Microvascular Type B Endothelin Receptor (ETBR) in Hypertensive Pregnancy
Author(s) -
Mazzuca Marc,
Mata Karina,
Khalil Raouf
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.810.5
Subject(s) - endocrinology , medicine , vasoconstriction , endothelin receptor , preeclampsia , biology , receptor , pregnancy , genetics
Preeclampsia is a form of hypertensive pregnancy (HTN‐Preg) with unclear mechanism. We have shown that localized reduction of uterine perfusion pressure (RUPP) in Preg rats is associated with downregulation of ET B R in mesenteric circulation, but the linking mechanisms are unclear. Placental ischemia increases circulating levels of anti‐angiogenic sFlt‐1. To test if sFlt‐1 is a mechanism linking RUPP to downregulation of vascular ET B R, day 14 Preg rats were either nontreated, or infused with sFlt‐1 10 μg/kg/day for 5 days (sFlt‐Preg), or underwent surgery to place clips on lower abdominal aorta and uterine arteries (RUPP). On day 19, BP was recorded and mesenteric microvessels were isolated to measure diameter and [Ca 2+ ] i (fura‐2 340/380 ratio). BP was in sFlt‐Preg 127±3 and RUPP 124±3 > Preg 101±3mmHg. ET‐1 (10 ‐7 M) caused vasoconstriction that was in sFlt‐Preg 66.1±3.0 and RUPP 71.3±5.4 > Preg 53.4±4.6%, and increase in [Ca 2+ ] i that was in sFlt‐Preg 0.90±0.01 and RUPP 0.89±0.01 > Preg (0.87±0.00). Endothelium‐removal or ET B R antagonist BQ‐788 enhanced ET‐1 vasoconstriction and [Ca 2+ ] i in Preg, but not sFlt‐Preg or RUPP. In microvessels preconstricted with phenylephrine, ET B R agonists sarafotoxin 6c and IRL‐1620 caused relaxation that was in sFlt‐Preg 4.2±1.0, 6.4±1.6% and RUPP 6.7±5.4, 9.5±3.3% < Preg 29.9±7.8, 28.0±9.1%. L‐NAME reduced ACh‐ and ET B R agonist‐induced relaxation in Preg, but not sFlt‐Preg or RUPP. Thus increased sFlt‐1 in Preg rats increases BP and ET‐1 microvascular constriction and decreases NO‐dependent and ET B R‐mediated vasodilation to levels similar to those in RUPP, suggesting that sFlt‐1 is a likely mechanism linking placental ischemia to downregulation of vascular ET B R in HTN‐Preg.