神经精神性高血压NE/机械力联合介导VSMC-α1-ARs信号加速促进移植静脉粥样硬化及机制探讨

项目名称： 神经精神性高血压NE/机械力联合介导VSMC-α1-ARs信号加速促进移植静脉粥样硬化及机制探讨

项目编号： No.81500337

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 刘树迎

作者单位： 中山大学

项目金额： 18万元

中文摘要： 神经精神因素导致交感-儿茶酚胺增加可引起应激性高血压，而临床上冠脉搭桥术后移植静脉再狭窄率10年约50%，神经精神因素是否与阻塞过程有关，目前无报道。我们研究发现：去甲肾上腺素（NE）与机械力单独刺激均可经由α1-肾上腺素能受体（α1-ARs）介导而激活ERKs，促进血管平滑肌细胞增殖，而两者联合刺激呈现协同效应。因此，本课题假设是：神经精神性高血压经由NE/机械力联合介导VSMC-α1-ARs信号加速促进移植静脉粥样硬化。拟在已有的专用于研究机械力与血管重构的体内、体外模型基础上，引入慢性应激性高血压模型，以α1-ARs为切入点，采用细胞生物学、生物化学、信号转导等技术，观察NE-机械力对血管重构的协同效应，探讨交感兴奋性NE+高血压机械力联合诱导的α1-ARs信号与血管重构之间的关系，阐明神经精神性高血压加速移植静脉粥样硬化病变的分子机制，为寻找防治移植静脉再狭窄的新药靶提供实验依据。

中文关键词： α1肾上腺素能受体；机械牵张力；血管平滑肌细胞；高血压；动脉粥样硬化

英文摘要： Increasing sympathetic-catecholamines exposed to psychosocial stress result in stress-induced hypertension, and vein graft restenosis rate within 10 years after coronary artery bypass grafting is about 50%, whether psychosocial stress is associated with restenosis, there are no reports available. we found that norepinephrine (NE) and mechanical stretch stress alone could activate the α1-adrenergic receptors (α1-ARs)/ERKs signal pathway and trigger increased proliferation in VSMCs, while the combined stimulation of both could trigger synergistic effects on ERKs activation and VSMC proliferation. So, we propose the hypothesis: α1-ARs mediate combined signals in VSMCs initiated by NE and mechanical stretch stress leading to accelerated vein graft atherosclerosis in neurogenic hypertension. On the basis of established in vivo and in vitro models for mechanical stretch stress and vascular remodeling, the chronic stress-induced hypertension animal model is introduced. Taking α1-ARs as starting point, cell biology, biochemistry and signal transduction techniques are adopted to observe the synergistic effect of NE and stretch stress on vascular remodeling, and to explore the relationship between α1-ARs signals and vascular remodeling induced by combined stimulation of NE owing to sympathetic overdrive and mechanical stretch stress induced by hypertension, and to elucidate the molecular mechanism of neurogenic hypertension to accelerate vein graft atherosclerosis after coronary artery bypass grafting. These findings would provide experimental evidence in seeking for new drug targets of vein graft restenosis.

英文关键词： α1 adrenergic receptor;mechanical stretch stress;vascular smooth muscle cell;hypertension;atherosclerosis