Antenatal Dexamethasone Exposure Impairs the High-Conductance Ca2+-Activated K+ Channels via Epigenetic Alteration at Gene Promoter in Male Offspring
Antenatal Dexamethasone Exposure Impairs the High-Conductance Ca2+-Activated K+ Channels via Epigenetic Alteration at Gene Promoter in Male Offspring
复制标题
产前地塞米松暴露通过雄性后代基因启动子的表观遗传改变损害高电导 Ca2 激活的 K 通道
DOI：
10.1161/atvbaha.120.314905
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发表时间：
2020-11-01
影响因子：
8.7
通讯作者：
Gao, Qinqin
中科院分区：
文献类型：
--
作者：
Xu, Ting;Zhao, Meng;Gao, Qinqin
补充数字内容可在文本中找到。目的：产前暴露于糖皮质激素会增加与后代血管功能障碍相关的心血管风险，但其潜在机制仍不清楚。高电导钙激活钾通道（BK）是一种重要的血管介质，在调节血管张力中起着重要作用。产前糖皮质激素对后代BK的长期影响在很大程度上是未知的。本研究探讨了产前暴露于临床相关剂量的糖皮质激素对后代血管BK的影响和机制。方法和结果：怀孕的Sprague-Dawley大鼠在怀孕的最后一周接受合成糖皮质激素地塞米松或车辆。在雄性后代（妊娠第21天[胎儿]和出生后第120天[成年后代]）的肠系膜动脉中检查血管功能、细胞电生理学、靶基因表达和启动子甲基化。孕期地塞米松暴露损害BK激活剂介导的舒张，并减少肠系膜动脉的全细胞BK电流。胎儿期地塞米松暴露不改变BK的Ca ~（2+）/电压敏感性，但可下调BK α和β1亚基在胎儿和成人肠系膜动脉中的表达。此外，BKα和BKβ1启动子甲基化的增加与这两个基因表达的减少相一致。结论：我们的研究结果表明，产前地塞米松暴露对血管BK通过改变从胎儿期到成年期的表观遗传模式的深远和长期的影响，促进了对产前糖皮质激素暴露对后代血管健康的长期不良影响和机制的理解。图形摘要：本文提供了图形摘要。
Supplemental Digital Content is available in the text. 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 Ca2+-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 Ca2+/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 pattern from fetal stage to adulthood, advancing understanding of prolonged adverse effects and mechanisms of antenatal glucocorticoids exposure on vascular health in offspring. Graphic Abstract: A graphic abstract is available for this article.