Long‐term high altitude hypoxia during gestation suppresses large conductance Ca²⁺‐activated K⁺ channel function in uterine arteries: a causal role for microRNA‐210

Abstract

Gestational hypoxia at high altitude has profound adverse effects on the uteroplacental circulation, and is associated with increased incidence of preeclampsia and fetal intrauterine growth restriction. Previous studies demonstrated that suppression of large-conductance Ca -activated K (BK ) channel function played a critical role in the maladaptation of uteroplacental circulation caused by gestational hypoxia. Yet, the mechanisms underlying gestational hypoxia-induced BK channel repression remain undetermined. The present study investigated a causal role of microRNA-210 (miR-210) in hypoxia-mediated repression of BK channel expression and function in uterine arteries using a sheep model. The results revealed that gestational hypoxia significantly decreased ten-eleven translocation methylcytosine dioxygenase 1 (TET1) expression in uterine arteries, which was recovered by inhibiting endogenous miR-210 with miR-210 locked nucleic acid (miR-210-LNA). Of importance, miR-210-LNA restored BK channel β1 subunit expression in uterine arteries, which was blocked by a competitive TET inhibitor, fumarate, thus functionally linking miR-210 to the TET1-BK channel cascade. In addition, miR-210-LNA reversed hypoxia-mediated suppression of BK channel function and rescued the effect of steroid hormones in upregulating BK channel expression and function in uterine arteries, which were also ablated by fumarate. Collectively, the present study demonstrates a causative effect of miR-210 in the downregulation of TET1 and subsequent repression of BK channel expression and function, providing a novel mechanistic insight into the regulation of BK channel function and the molecular basis underlying the maladaptation of uterine vascular function in gestational hypoxia.

Effect of Oxidative Stress on the Estrogen-NOS-NO-KCa Channel Pathway in Uteroplacental Dysfunction: Its Implication in Pregnancy Complications

“…HIF-1 α overexpression in uteroplacental tissues is a characterized feature in pregnancy complications and high-altitude pregnancy [157, 233, 234]. Both ex vivo hypoxia treatment of tissues or pharmacologically induced hypoxia in intact animal models induced the expression of DNMTs and miR-210 [142, 225, 235] and repressed both histone demethylase activity [231] and TETs expression/activity [235, 236]. Although not investigated in the uteroplacental tissues, studies conducted in other tissues/cells suggest that hypoxia-induced alterations in epigenetic machineries is HIF-1 α -dependent.…”

Pregnancy-Related Acute Kidney Injury at High Altitude: A Retrospective Observational Study in a Single Center

“…Hypoxia regulates the production of numerous vascular endothelial regulatory factors known to in uence vascular function during pregnancy and/or to be associated with preeclampsia, including endothelin-1, thromboxane A2, prostacyclin and tumor necrosis factor alpha [36] . Animal experiments also con rm that long-term high altitude hypoxia during gestation suppresses large conductance Ca2+-activated K+(BKCa) channel function in uterine arteries, which is of critical importance in pregnancy-mediated increase in uterine artery vasodilation and blood ow, resulting in the dysfunction of uterine placental circulation and the development of preeclampsia [37] . Hypoxia can also activate placental renin-angiotensin system, leading to placental dysfunction and oxidative stress response, which enhance the vasoconstrictor effect of locally-generated angiotensin II and contribute to the restricted fetal growth characteristic of preeclampsia [38][39] .…”

The newborn sheep translational model for pulmonary arterial hypertension of the neonate at high altitude

“…2,17,21,31,34 The sheep has been used as a model that represents an animal not adapted to high altitude, such as the human species. 21,30,[42][43][44][45][46][47][48][49] Pregnant women and their unborn babies from several regions of the world are chronically exposed to the low-oxygen milieu of high-altitude mountains or plateaus. 21,50,51 Pregnancy at high altitude is clearly a potential burden for both mother and fetus.…”