Antenatal Dexamethasone Exposure Impairs the High-Conductance Ca 2+ -Activated K + Channels via Epigenetic Alteration at Gene Promoter in Male Offspring

作者：Ting Xu, Meng Zhao, Huan Li, Xiuwen Zhou, Bailin Liu, Miao Sun, Zhice Xu, Qinqin Gao · 发表于：Arteriosclerosis Thrombosis and Vascular Biology · 年份：2020 · DOI：10.1161/atvbaha.120.314905 · 被引用次数：20 · 研究领域：Stress Responses and Cortisol、Neonatal Respiratory Health Research、Ion channel regulation and function

Objective: Antenatal exposure to glucocorticoids increases cardiovascular risks related to vascular dysfunctions in offspring, although underlying mechanisms are still unknown. As an important vascular mediator, high-conductance Ca 2+ -activated K + channels (BK) plays an essential role in determining vascular tone. Long-term effects of antenatal glucocorticoids on BK in offspring are largely unknown. This study examined the effects and mechanisms of antenatal exposure to clinically relevant doses of glucocorticoids on vascular BK in offspring. Approach and Results: Pregnant Sprague-Dawley rats received synthetic glucocorticoids dexamethasone or vehicle during the last week of pregnancy. Vascular functions, cellular electrophysiology, target gene expression, and promoter methylation were examined in mesenteric arteries of male offspring (gestational day 21 [fetus] and postnatal day 120 [adult offspring]). Antenatal dexamethasone exposure impaired BK activators-mediated relaxation and reduced whole-cell BK currents in mesenteric arteries. Antenatal dexamethasone exposure did not alter Ca 2+ /voltage-sensitivity of BK but downregulated the expressions of BK α and β1 subunits in both fetal and adult mesenteric arteries. In addition, increased promoter methylations within BKα and BKβ1 were compatible with reduced expressions of the 2 genes. Conclusions: Our findings showed a profound and long-term impact of antenatal dexamethasone exposure on vascular BK via an altered epigenetic...