Antenatal Hypoxia Affects Pulmonary Artery Contractile Functions via Downregulating L-type Ca(2+) Channels Subunit Alpha1 C in Adult Male Offspring.
Antenatal Hypoxia Affects Pulmonary Artery Contractile Functions via Downregulating L-type Ca(2+) Channels Subunit Alpha1 C in Adult Male Offspring.
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DOI：
10.1161/jaha.120.019922
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发表时间：
2021-04-20
影响因子：
5.4
通讯作者：
Gao Q
中科院分区：
文献类型：
--
作者：
Li H;Ji B;Xu T;Zhao M;Zhang Y;Sun M;Xu Z;Gao Q
胎儿宫内缺氧是一种常见的妊娠并发症，对个体日后的血管健康有深远的不利影响。肺动脉对缺氧敏感，但产前缺氧对子代肺血管反应性的不良影响尚不清楚。本研究旨在探讨产前缺氧对成年雄性子代肺动脉功能的影响及其相关机制。从妊娠第10天至第20天，将妊娠Sprague-道利大鼠饲养在常氧或低氧（10.5% O2）室中。雄性后代在16周龄时被安乐死（成年后代）。收集肺动脉进行血管功能、电生理学、靶基因表达和启动子甲基化研究。在肺动脉环中，产前缺氧后代对盐酸5-羟色胺、血管紧张素II或苯肾上腺素的收缩减少，这是由失活的L-型Ca2+通道引起的。在肺动脉平滑肌细胞中，基础全细胞Ca2+电流以及血管收缩剂诱导的Ca2+瞬变在产前缺氧后代中显著降低。此外，L-型Ca2+通道亚基alpha1 C内启动子甲基化的增加与其表达的减少是相容的。这项研究表明，产前缺氧编程长期持续的血管收缩功能减退的男性后代，这是与肺动脉中的L-型钙通道亚基alpha1 C的减少。胎儿缺氧导致出生后后代的肺动脉不良结局，通过DNA甲基化介导的表观遗传机制与重编程L型Ca2+通道亚基α 1 C表达密切相关，促进了对早期生命中胎儿缺氧对长期血管健康影响的理解。
Antenatal intrauterine fetal hypoxia is a common pregnancy complication that has profound adverse effects on an individual's vascular health later in life. Pulmonary arteries are sensitive to hypoxia, but adverse effects of antenatal hypoxia on pulmonary vasoreactivities in the offspring remain unknown. This study aimed to determine the effects and related mechanisms of antenatal hypoxia on pulmonary artery functions in adult male offspring. Pregnant Sprague‐Dawley rats were housed in a normoxic or hypoxic (10.5% O2) chamber from gestation days 10 to 20. Male offspring were euthanized at 16 weeks old (adult offspring). Pulmonary arteries were collected for vascular function, electrophysiology, target gene expression, and promoter methylation studies. In pulmonary artery rings, contractions to serotonin hydrochloride, angiotensin II, or phenylephrine were reduced in the antenatal hypoxic offspring, which resulted from inactivated L‐type Ca2+ channels. In pulmonary artery smooth muscle cells, the basal whole‐cell Ca2+ currents, as well as vasoconstrictor‐induced Ca2+ transients were significantly reduced in antenatal hypoxic offspring. In addition, increased promoter methylations within L‐type Ca2+ channel subunit alpha1 C were compatible with its reduced expressions. This study indicated that antenatal hypoxia programmed long‐lasting vascular hypocontractility in the male offspring that is linked to decreases of L‐type Ca2+ channel subunit alpha1 C in the pulmonary arteries. Antenatal hypoxia resulted in pulmonary artery adverse outcomes in postnatal offspring, was strongly associated with reprogrammed L‐type Ca2+ channel subunit alpha1 C expression via a DNA methylation‐mediated epigenetic mechanism, advancing understanding toward the effect of antenatal hypoxia in early life on long‐term vascular health.