Endothelin-Dependent Vasoconstriction in Human Uterine Artery: Application to Preeclampsia

Abstract

BackgroundReduced uteroplacental perfusion, the initiating event in preeclampsia, is associated with enhanced endothelin-1 (ET-1) production which feeds the vasoconstriction of uterine artery. Whether the treatments of preeclampsia were effective on ET-1 induced contraction and could reverse placental ischemia is the question addressed in this study. We investigated the effect of antihypertensive drugs used in preeclampsia and of ET receptor antagonists on the contractile response to ET-1 on human uterine arteries.Methodology/Principal FindingsExperiments were performed, ex vivo, on human uterine artery samples obtained after hysterectomy. We studied variations in isometric tension of arterial rings in response to the vasoconstrictor ET-1 and evaluated the effects of various vasodilators and ET-receptor antagonists on this response. Among antihypertensive drugs, only dihydropyridines were effective in blocking and reversing the ET-1 contractile response. Their efficiency, independent of the concentration of ET-1, was only partial. Hydralazine, alpha-methyldopa and labetalol had no effect on ET-1 induced contraction which is mediated by both ETA and ETB receptors in uterine artery. ET receptors antagonists, BQ-123 and BQ-788, slightly reduced the amplitude of the response to ET-1. Combination of both antagonists was more efficient, but it was not possible to reverse the maximal ET-1-induced contraction with antagonists used alone or in combination.ConclusionPharmacological drugs currently used in the context of preeclampsia, do not reverse ET-1 induced contraction. Only dihydropyridines, which partially relax uterine artery previously contracted with ET-1, might offer interesting perspectives to improve placental perfusion.

Preeclampsia serum-induced collagen I expression and intracellular calcium levels in arterial smooth muscle cells are mediated by the PLC-γ1 pathway

“…Although the present study did not determine the molecule in the PE sera that induced the responses in HUASMCs either directly or indirectly via HUVECs, Steinert et al 37 suggested that a monooxygenase metabolite may be responsible for the increased [Ca 2+ ] i observed in PE HUASMCs. Moreover, the presence of inotropic vasoactive substances, including Ang-II and ET-1, in the serum of PE patients has been detected; 41 , 42 , 43 , 44 however, it is not clear whether these substances are derived from the placenta or injured vascular ECs. ET-1 can regulate smooth muscle cell proliferation 45 and induce endoplasmic reticulum stress via the PLC-IP 3 pathway in PE; 46 however, ET-1 or Ang-II alone fails to explain the pathogenesis of vascular disease in PE patients.…”

Pre-eclampsia following chemotherapy for breast cancer during pregnancy: case report and review of the literature

“…A disordered conversion of trophoblast from an epithelial to an endothelial phenotype [19,20] leads to abnormal release of placental factors into the maternal circulation [21,22]. This initially leads to local endothelial dysfunction and vasoconstriction of the uterine arteries [23,24], which could further lead to a generalized endothelial dysfunction and produce the maternal signs. The central role in the pathogenesis of pre-eclampsia is probably the resultant inequality between the endogenous placental products, some of which are antiangiogen such as soluble fms-like tyrosinkinase 1 (sFLT-1) and soluble endoglin (sEndoglin), and others such as the proangiogen placental growth factor (PIGF) [12,[25][26][27] as their presence is correlated [27,28].…”

Role of Endothelin in Uteroplacental Circulation and Fetal Vascular Function

“…Numerous studies have shown that ET receptor antagonists [37, 128] and nitric oxide [33, 129] can inhibit vasoconstriction induced by high levels of ET expression. It has been suggested that ECE-1 may be a useful target for treating hypertensive diseases due to its key role in converting ET-1 into its active form [32, 130].…”