WSS-H2O2-NOX-SVV轴致血管内膜增生中的作用及机制
批准号:
81770289
项目类别:
面上项目
资助金额:
55.0 万元
负责人:
王学虎
依托单位:
学科分类:
H0202.心肌损伤、修复、重构和再生
结题年份:
2021
批准年份:
2017
项目状态:
已结题
项目参与者:
赵渝、王婧、朱方玉、张灏龙、曾秋、王哲、杨志鹏
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中文摘要
内膜增生是动脉硬化闭塞以及动脉术后再狭窄的重要原因。增生的机制复杂,与血流动力学改变以及血管的顺应性有关,具体机制仍不明确。研究发现血管壁切应力(WSS)及血管壁环压(CS)通过H2O2-NADPH氧化酶(NOX)等途径引起内皮细胞和血管平滑肌细胞功能失调,从而启动内膜的增生,但具体过程仍需进一步研究。 本研究拟建立切应力及管壁环压两种血管壁受力模型,模拟病理学情况下血管壁剪切力,环压的变化,检测狭窄不同部位内膜增生厚度、内皮细胞功能、平滑肌细胞表型变化、炎症细胞浸润程度等之间差异,明确狭窄程度对内膜增生的影响;同时研究血流动力学异常相关NOX调控血管内皮细胞和平滑肌细胞的生物学功能变化;进而采用蛋白质组学研究方法,探索NOX相关更多调控蛋白,以补充和细化其调控通路,评估这种血流动力学异常与内膜增生的关系以及调控关键靶点。明确血流动力学调控机制,为进一步临床干预提控理论依据。
英文摘要
Atherosclerosis is a common disease in old people. Intimal hyperplasia is the important reason of the arteries occlusion and postoperative restenosis. Intimal hyperplasia mechanism is complex and not random. Intimal hyperplasia often appears at bifurcate artery and the place of vascular anastomosis. This is associated with hemodynamic change and vascular compliance, but the relationship between the degree of narrow and the stimulation of intimal hyperplasia is still not clear. Nowadays, study have found that the Wall shear stress (WSS) change affect the way such as H2O2-NADPH oxidase (NOX) to result to the cell function disorder, eventually lead to endometrial hyperplasia. Although H2O2 is defined as an ROS, unlike O2- it is not a free radical, in that it does not possess an unpaired electron in its outer shell. This renders H2O2 more stable and less reactive with other issue radicals and, thus, a more likely paracrine ROS. This study intends to establish animal artery narrow models and stent implantation models with the different degree, test the degree of narrow area, Wall shear tress, Circumferential strain, hyperplasia of endometrium thickness around the narrow area, smooth muscle cell phenotypic changes, the difference between degree of inflammatory cell infiltration, to clear the relationship between stenosis degree and endometrial hyperplasia, to clear the relationship between hemodynamic abnormalities with NOX biological function of vascular endothelial cells and smooth muscle cells. In addition, we will use the proteomics method to verify and find the new relevant mechanism of regulatory proteins, to develop other regulatory pathways and provide the theoretical and experimental basis for further clinical intervention.
内膜增生(IH)是动脉硬化闭塞以及术后再狭窄的重要原因。增生的机制复杂,与血流动力学改变以及血管的顺应性有关,具体机制仍不明确。研究发现血管壁切应力(WSS)及血管壁环压(CS)通过H2O2-NADPH氧化酶(NOX)等途径引起内皮细胞和血管平滑肌细胞功能失调,从而启动内膜的增生,但具体过程仍需进一步阐明。首先,本研究采用动脉缩窄术建立不同程度颈动脉狭窄的动物模型,发现狭窄程度≥50%时WSS显著升高,从而激活NOX产生ROS及其下游的AKT-SVV(存活素)诱导、促进IH。在体外,利用外源性H2O2刺激人主动脉平滑肌细胞(HASMCS)可诱导其增殖、迁移并抑制其凋亡。初步界定动脉狭窄临界点为50%,超过此界限可导致过高的WSS,通过NOX-AKT-SVV轴影响动脉血管内皮细胞及平滑肌细胞功能而介导动脉血管重构。其次,在体外,我们采用自制的压力加载装置,将不同梯度的跨壁压力(TP)作用于HASMCs,结果表明,当加载压力>160 mmHg时,TP亦可通过与NOX、SVV相关的机制驱动HASMCs增殖。因此,我们的研究结果表明WSS/TP-NOX-H2O2-AKT-SVV轴可能是防治IH相关疾病的潜在靶点,为临床干预治疗IH相关疾病提供一些理论和实验基础。
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
Wall shear stress promotes intimal hyperplasia through the paracrine H2O2-mediated NOX-AKT-SVV axis
壁剪切应力通过旁分泌 H2O2 介导的 NOX-AKT-SVV 轴促进内膜增生
DOI:10.1016/j.lfs.2018.05.045
发表时间:2018
期刊:Life Sciences
影响因子:6.1
作者:Zhang Haolong;Yang Zhipeng;Wang Jing;Wang Xuehu;Zhao Yu;Zhu Fangyu
通讯作者:Zhu Fangyu
Transmural pressure drives proliferation of human arterial smooth muscle cells via mechanism associated with NADPH oxidase and Survivin (vol 126, 103905, 2019)
跨壁压力通过与 NADPH 氧化酶和生存素相关的机制驱动人动脉平滑肌细胞增殖(第 126 卷、103905、2019)
DOI:10.1016/j.mvr.2019.103960
发表时间:2020
期刊:Microvascular Research
影响因子:3.1
作者:Ran Kun;Yang Zhipeng;Zhao Yu;Wang Xuehu
通讯作者:Wang Xuehu
SVV基因调控下的血管内皮细胞在治疗外周缺血性疾病中的应用及机制研究
- 批准号:81200230
- 项目类别:青年科学基金项目
- 资助金额:23.0万元
- 批准年份:2012
- 负责人:王学虎
- 依托单位:
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