CTRP1促进紊流下动脉内皮屏障功能损伤及其机制研究

Atherosclerotic lesions preferentially occur at branch pointes of arterial trees where the blood flow is disturbed. Disturbed flow increases endothelial permeability, vascular barrier dysfunction, and finally the development of atherosclerosis. CTRP1, a member of C1q/TNF related protein (CTRP) family, is a novel secreted glycoprotein and its biological functions are largely undefined. By using microarray analysis, we found disturbed flow significantly increased the expression of CTRP1. We also discovered that CTRP1 induces endothelial hyperpermeability by promoting cytoskeleton assembly and the formation of paracellular holes. To further prove that disturbed flow-induced endothelial hyperpermeability is mediated by CTRP1, we successfully established the CTRP1 knockout mice. In our next step, we will investigate whether inhibition of CTRP1 attenuates endothelial barrier dysfunction and the development of atherosclerosis, either by using the CTRP1 knockout mice or by intravenous injection of CTRP1 neutralizing antibodies. We will also identify the precise molecular mechanisms by which CTRP1 modulates endothelial permeability. We believe that our study will aid the design of new strategies in clinical practice to inhibit the pathogenesis of atherosclerosis in early stage.

动脉粥样硬化斑块好发于血管分叉及分支处，这些部位的血流动力学紊乱，产生以反流、涡流等为特征的紊流。紊流促进动脉内皮通透性增加和屏障功能破坏，最终导致了粥样硬化的病理发生。CTRP1隶属于CTRP家族，是一种具有血管生物学活性的分泌性糖蛋白。通过基因芯片分析我们发现，紊流作用下血管内皮中CTRP1的表达和分泌水平显著上升，进一步研究显示CTRP1可促进内皮细胞骨架聚集、细胞间隙增宽，增加了血管内皮对循环中的大分子物质通透性。为了直接验证紊流、CTRP1和内皮通透性增加三者之间的因果联系，我们已经成功建立了CTRP1基因敲除小鼠模型，我们下一步将充分利用该小鼠模型和CTRP1的中和抗体，深入分析CTRP1的表达缺失能否缓解紊流区域血管内皮屏障功能损伤和和粥样斑块形成，我们还将进一步完善机制探讨，揭示CTRP1促进内皮通透性增加的精确分子机制，为能在早期干预动脉粥样硬化发生提供新的靶点和途径。

动脉粥样硬化斑块好发于血管分叉及分支处，该部位的血流动力学紊乱，产生以返流、涡流等为特征的紊流。紊流促进动脉内皮功能不全和血管屏障功能损伤，最终促进了动脉粥样硬化的病理发生。本课题组通过基因芯片筛选，发现紊流作用区域血管内皮细胞新脂肪因子CTRP1的表达和分泌水平显著上升。通过建立CTRP1基因敲除和过表达小鼠模型，本课题组首次发现：1）CTRP1是促进血管壁炎症和动脉粥样病变的重要介质。CTRP1可通过增加循环中白细胞与血管内皮的相互作用，增加炎性细胞浸润，促进粥样斑块进展。2）紊流作用下血管内皮细胞CTRP1的表达和分泌显著增加，可通过激活VEGFR2受体增加血管壁对大分子物质的通透性，而应用中和抗体阻断CTRP1则能改善紊流下血管内皮屏障功能损伤。3）单核细胞转化为巨噬细胞时CTRP1表达显著上调，并介导吞噬oxLDL后多种促炎介质的分泌。4）CTRP1通过抑制一氧化氮合成，抑制内皮依赖性血管舒张。该系列研究证实新脂肪因子CTRP1通过促进内皮细胞功能不全和巨噬细胞炎症，导致动脉血管功能和结构损伤，并参与剪切力血管功能调节，促进动脉粥样硬化的病理发生。通过基因敲除或中和抗体阻断CTRP1，则能显著改善动物模型中血管壁损伤和斑块进展，具有潜在的临床转化价值。相关研究成果有多篇SCI论文发表，并多次在心血管国际会议上汇报交流，并获得省部级人才项目资助。