Yun He, Ze Zhang, Qiutong Zheng, Hongyu Su, Mingxing Liu, Xueyi Chen, Linglu Qi, Yumeng Zhang, Zhice Xu, Jiaqi Tang
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引用次数: 0
Abstract
Background: Paternal preconception alcohol exposure affects fetal development; however, it is largely unknown about the influences on offspring vasculature and mechanisms.
Methods: Offspring born form paternal rats treated with alcohol or water before pregnant was raised until 3 months of age. Vessel tone of mesenteric arteries was detected using myograph system; whole-cell calcium channel current in smooth muscle cells was tested using patch-clamp; molecule expressions were detected with real-time PCR, western blotting, and Dihydroethidium (DHE); DNA methylations were determined using targeted bisulfate sequencing assay. Following 5-aza-2'-deoxycytidine incubation, vessel tone in offspring mesenteric artery and Cacna1c expression in A7r5 was tested.
Results: When comparing with the control, stress-strain curve was left-shifted in alcohol. There was lower incremental distensibility and endothelium-dependent dilation associated with endothelial nitric oxide synthase. Agonists-induced constrictions were greater in alcohol offspring than that in control, associated with higher expression of AT1R, Cacna1c, and reactive oxygen species (ROS). Baseline and Ang II-stimulated calcium channel currents were higher in alcohol group. Tempol and apocynin could restore Ang II-increased constriction and calcium channel current in alcohol offspring. When comparing with the control, there was lower DNA methylation of Cacna1c promotor in alcohol offspring mesenteric artery and in paternal sperm. 5-aza-2'-deoxycytidine increased contraction in control offspring mesenteric artery and Cacna1c expression in A7r5.
Conclusion: Paternal preconception alcohol exposure-affected offspring mesenteric artery was via ROS-Cacna1c. Abnormal offspring vascular functions might be inherited via DNA hypomethylation of Cacna1c promotor from paternal sperm exposed to alcohol. These data gained provided important clues for cardiovascular disorders at germ cell origin.
背景：父亲孕前酒精暴露影响胎儿发育；然而，对后代脉管系统的影响及其机制尚不清楚。方法：将怀孕前用酒精或水处理的母鼠所生的子代饲养至3月龄。肌图系统检测肠系膜动脉血管张力；膜片钳法检测平滑肌细胞全细胞钙通道电流；采用实时荧光定量PCR、western blotting和双氢乙啶（DHE）检测分子表达；采用靶向硫酸氢盐测序法测定DNA甲基化。5-aza-2'-脱氧胞苷孵育后，检测子代肠系膜动脉血管张力和A7r5中Cacna1c的表达。结果：与对照组相比，酒精中应力-应变曲线左移。内皮型一氧化氮合酶有较低的增量扩张性和内皮依赖性扩张性。酒精后代中激动剂诱导的收缩比对照组更大，与AT1R、Cacna1c和活性氧（ROS）的高表达有关。酒精组基线和angii刺激的钙通道电流较高。天麻酚和罗布麻素可恢复酒精后代Ang ii -升高的收缩和钙通道电流。与对照组相比，酒精后代肠系膜动脉和父亲精子中Cacna1c启动子的DNA甲基化水平较低。5-aza-2'-脱氧胞苷增加了对照子代肠系膜动脉收缩和A7r5中Cacna1c的表达。结论：父亲孕前酒精暴露通过ROS-Cacna1c影响子代肠系膜动脉。后代血管功能异常可能是通过暴露于酒精的父亲精子中Cacna1c启动子的DNA低甲基化遗传的。这些数据为生殖细胞起源的心血管疾病提供了重要线索。
期刊介绍：
The Journal of Hypertension publishes papers reporting original clinical and experimental research which are of a high standard and which contribute to the advancement of knowledge in the field of hypertension. The Journal publishes full papers, reviews or editorials (normally by invitation), and correspondence.
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