孕期有氧运动对高血压子代血管功能的重编程：代谢参与的A激酶锚定蛋白DNA甲基化机制

孕期不良宫内环境可致子代成年后多种慢性疾病易感，而良好生活方式（运动）可否对原发性高血压子代产生良性印迹尚未可知。A激酶锚定蛋白AKAP150可将多种酶聚集于特定细胞区域提高转导效率，在高血压血管重构中发挥着重要作用。我们近期研究发现运动可有效抑制自发性高血压大鼠SHR血管平滑肌AKAP150，下调CaV1.2通道功能，诱导动脉舒张。然而孕期母亲运动可否对高血压子代AKAP150重编程，经兴奋转录耦联AKAP/CaN/NFATc3抑制血管平滑肌表型转换尚不清楚，而这对高血压生命早期防治具有重要意义。本项目从子代胎儿和成年两个阶段着手，选用SHR及Akap5平滑肌条件性基因敲入模型，探讨孕期运动是否可经该基因启动子区甲基化诱导高血压子代血管功能改善；此作用是否由能量感受器AMPK诱导的SAM/SAH变化介导，进而揭示孕期运动对子代血管的长期效应及代谢-表观遗传机理，为高血压防治寻求新出口。

The view that an adverse intrauterine environment during pregnancy contributes to poor long-term health in the offspring is well established. However, whether maternal good lifestyle such as exercise can produce a benign imprinting on the offspring of essential hypertension is largely unknown. A-kinase anchoring protein AKAP150 can assemble multifunctional signaling enzymes to precise subcellular compartments, and improve the signal transduction efficiency, which plays important role in the vascular remodeling of hypertension. Our recent study demonstrated that aerobic exercise can efficiently inhibit AKAP150, downregulate the CaV1.2 channel function, and induce the vasodilation in spontaneously hypertensive rats (SHR). However, it is not clear whether maternal exercise during pregnancy can cause reprogramming of AKAP150 signaling pathway and inhibit the phenotype switching in vascular smooth muscle cells in hypertensive offspring through the excitation-transcription coupling (AKAP/CaN/NFATc3) mechanism. To clarify this is very important for us to understand the prevention and treatment of hypertension in the early stage of life. Therefore, by using SHR and a mouse model of conditional smooth muscle-specific knock-in Akap5 gene, the project aims to investigate that whether maternal exercise during pregnancy can improve the vascular function by DNA methylation of the promoter of Akap5 gene in SHR offspring; whether these effects are mediated by the energy sensor AMP-activated protein kinase (AMPK)-induced SAM/SAH change. The information gained will help us understand the long-term effect and metabolism-epigenetic mechanism of the pregnancy exercise on the vasculature of the hypertensive offspring, which may be a new strategy for prevention and control of hypertension.