Abstract：
Perinatal high-fat diets (PHF) can influence fetal/neonate development, resulting in cardiovascular pathogenesis, but precise mechanisms remain unclear. This study tests aldosterone receptor-mediated Ca2+ influx and the underlying mechanisms influenced by PHF.
Maternal S.D. rats receive PHF during pregnancy and lactation periods. Their male offspring are fed normal diets after weaning for four months. Mesenteric arteries (MA) are for electrophysiological testing, Ca2+ imaging, target gene expression, and promotor methylation. PHF increases aldosterone receptor gene Nr3c2-mediated Ca2+ currents in the smooth muscle cells (SMCs) of the MA via L-type Ca2+ channels (LTCC) in the offspring. The increased expression of aldosterone-receptors and LTCC are responsible for an activated Nr3c2-LTCC pathway in the vasculature, eventually predisposes an increase of Ca2+ influx in the myocytes of resistance arteries. The inhibitor of aldosterone-receptors suppresses the increased Ca2+ currents in the SMCs. Nr3c2 and LTCC are upregulated through the transcriptional mechanism in methylation, which can be reversed in the functional changes by methylation inhibitor 5AZA.
The results firstly demonstrate that aldosterone-receptor activation can stimulate Ca2+ currents via LTCC in vascular myocytes, which can be altered by perinatal foods via epigenetic changes of DNA methylation in the promoters of Nr3c2 and LTCC.
Maternal S.D. rats receive PHF during pregnancy and lactation periods. Their male offspring are fed normal diets after weaning for four months. Mesenteric arteries (MA) are for electrophysiological testing, Ca2+ imaging, target gene expression, and promotor methylation. PHF increases aldosterone receptor gene Nr3c2-mediated Ca2+ currents in the smooth muscle cells (SMCs) of the MA via L-type Ca2+ channels (LTCC) in the offspring. The increased expression of aldosterone-receptors and LTCC are responsible for an activated Nr3c2-LTCC pathway in the vasculature, eventually predisposes an increase of Ca2+ influx in the myocytes of resistance arteries. The inhibitor of aldosterone-receptors suppresses the increased Ca2+ currents in the SMCs. Nr3c2 and LTCC are upregulated through the transcriptional mechanism in methylation, which can be reversed in the functional changes by methylation inhibitor 5AZA.
The results firstly demonstrate that aldosterone-receptor activation can stimulate Ca2+ currents via LTCC in vascular myocytes, which can be altered by perinatal foods via epigenetic changes of DNA methylation in the promoters of Nr3c2 and LTCC.
摘要：
方法：围产期高脂饮食（PHF）可以影响胎儿/新生儿的发育，导致心血管发病机制，但确切的机制仍不清楚。这项研究测试了醛固酮受体介导的Ca2流入以及PHF影响的潜在机制。
结果：母鼠在妊娠期和哺乳期接受PHF。他们的雄性后代在断奶四个月后被喂食正常的饮食。肠系膜动脉（MA）用于电生理测试，Ca2+成像，靶基因表达,和启动子甲基化。PHF通过后代的L型Ca2通道（LTCC）增加MA的平滑肌细胞（SMC）中醛固酮受体基因Nr3c2介导的Ca2电流。醛固酮受体和LTCC的表达增加是血管中激活的Nr3c2-LTCC通路的原因，最终会导致阻力动脉肌细胞中Ca2内流的增加。醛固酮受体的抑制剂抑制SMC中增加的Ca2电流。Nr3c2和LTCC通过甲基化的转录机制上调，甲基化抑制剂5AZA可以逆转其功能变化。
结论：结果首先表明，醛固酮受体激活可以通过LTCC刺激血管肌细胞中的Ca2电流，围产期食物可以通过Nr3c2和LTCC启动子中DNA甲基化的表观遗传变化来改变。
结果：母鼠在妊娠期和哺乳期接受PHF。他们的雄性后代在断奶四个月后被喂食正常的饮食。肠系膜动脉（MA）用于电生理测试，Ca2+成像，靶基因表达,和启动子甲基化。PHF通过后代的L型Ca2通道（LTCC）增加MA的平滑肌细胞（SMC）中醛固酮受体基因Nr3c2介导的Ca2电流。醛固酮受体和LTCC的表达增加是血管中激活的Nr3c2-LTCC通路的原因，最终会导致阻力动脉肌细胞中Ca2内流的增加。醛固酮受体的抑制剂抑制SMC中增加的Ca2电流。Nr3c2和LTCC通过甲基化的转录机制上调，甲基化抑制剂5AZA可以逆转其功能变化。
结论：结果首先表明，醛固酮受体激活可以通过LTCC刺激血管肌细胞中的Ca2电流，围产期食物可以通过Nr3c2和LTCC启动子中DNA甲基化的表观遗传变化来改变。
