Overexpression of the SK3 channel alters vascular remodeling during pregnancy, leading to fetal demise

摘要

Potassium channels regulate vascular smooth muscle dilation, proliferation, and angiogenesis (19) and thus can be a contributing factor in vascular remodeling diMng pregnancy. The small conductance Ca~(2+)-activated K~+ channel subtype 3 (SK3 channel) has emerged as an important ionic regulator of membrane excitability during pregnancy. Transgenic Kcnn3~(tm1Jpad)/Kcnn3~(tm1Jpad) (SK3~(T/T)) knock-in mice, which exhibit approximately threefold increased expression of the SK3 channel, have compromised parturition (2, 21). Another notable phenotype of the SK3~(T/T) mice is abnormal vessel branching, and increased diameters, of mesenteric arteries (28). Although the SK3 channel is absent in vascular smooth muscle, it is abundant in endothelial cells, where its primary role is to modulate arterial tone and blood pressure (4, 28). In this context, the SK3 channel contributes to sustained hyperpolar-ization of the endothelial membrane potential, which is conveyed through diffusible factors to the membranes of the vascular smooth muscle cells. Endothelial SK3 channels have a substantial tonic influence on vascular tone in the absence of any exogenous endothelial stimulation (28). SK3 channels mediate endothelium-dependent hyperpolarizing factor (EDHF)-induced vascular relaxation, and blocking SK3 channels nearly abolishes EDHF-induced vasodilation in human systemic omental and myometrial arteries (9) and late-pregnant rat uteroplacental resistance vessels (43). For this reason, the SK3 channel is thought to be a potential target for pregnancy-related vascular diseases, like preeclampsia, in which patients have abnormal EDHF-mediated vasodilation (9).