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Role of proteinase-activated receptors in the dysregulation of vascular tone and the enhancement of the proliferative state in vascular lesions

蛋白酶激活受体在血管张力失调和血管病变增殖状态增强中的作用

基本信息

批准号：
17590744
负责人：
HIRANO Katsuya
金额：
$ 2.24万
依托单位：
KYUSHU UNIVERCITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

Thrombus formation plays a critical role in the pathogenesis and pathophysiology of various vascular diseases. Proteinases, such as thrombin, activate proteinase-activated receptors (PARs), thereby exerting the vascular effects, including vasoconstriction, smooth muscle proliferation, vascular hyper-permeability, and production of the endothelium-derived vasoactive substances. However, the roles of PARs in the pathogenesis and pathophysiology of vascular diseases still remain to be elucidated. In the present study, we advanced our earlier studies on the physiological roles of PARs in the regulation of vascular function, and thereby investigated the pathophysiological role of PARs in vascular diseases. Especially, we focused our special attention on the regulation of vascular tone and proliferation, which play a central role in the pathophysiology of vascular diseases. We investigated the role of PARs in the vasospastic response after balloon injury; the role of thrombin and PAR1 in pos … More t-hemorrhagic vasospasm in subarachnoid hemorrhage; the thrombin-mediated vascular tone regulation in the normal pulmonary artery. We investigated the changes in the expression of PARs, the response to PAR agonists, and the signal transduction mechanisms under pathological conditions. We also investigated the molecular mechanisms underlying the endothelial NO production mediated by PAR1 and PAR4. Consequently, we clarified for the first time, (1) Rac1 regulatesd the cell-surface expression of PAR1 by activating the membrane trafficking ; (2) Balloon injury up-regulated the expression of PAR1 and PAR2, thereby enhancing the contractile response to thrombin and trypsin ; (3) Thrombin induced the up-regulation of PAR1 and the enhancement of the contractile response to thrombin in subarachnoid hemorrhage ; (4) Thrombin induced the vasoconstriction in the normal pulmonary artery by elevating [Ca^<2+>]_i and the Ca^<2+> sensitivity of the contractile apparatus ; (5) The activation of PAR4 induced endothelial NO production in a manner independent of the Ca^<2+> signal, and dependent on the phosphatidylinositol 3-kinase/Akt pathway. Less

血栓形成在各种血管疾病的发病机制和病理生理中起着至关重要的作用。凝血酶等蛋白酶激活蛋白酶活化受体（PARs），从而发挥血管作用，包括血管收缩、平滑肌增生、血管超通透性和内皮源性血管活性物质的产生。然而，PARs在血管疾病的发病机制和病理生理中的作用仍有待阐明。本研究在前期研究PARs在血管功能调控中的生理作用的基础上，进一步探讨PARs在血管疾病中的病理生理作用。我们特别关注血管张力和增殖的调节，这在血管疾病的病理生理中起着核心作用。我们研究了PARs在球囊损伤后血管痉挛反应中的作用；凝血酶和PAR1在蛛网膜下腔出血t-出血性血管痉挛中的作用凝血酶介导的正常肺动脉血管张力调节。我们研究了病理条件下PARs的表达变化、对PARs激动剂的反应以及信号转导机制。我们还研究了PAR1和PAR4介导内皮细胞NO生成的分子机制。因此，我们首次明确了：(1)Rac1通过激活膜运输调节PAR1的细胞表面表达；(2)球囊损伤可上调PAR1和PAR2的表达，从而增强对凝血酶和胰蛋白酶的收缩反应；(3)凝血酶诱导蛛网膜下腔出血时PAR1表达上调，凝血酶收缩反应增强；(4)凝血酶通过提高[Ca^<2+>] i和收缩器Ca^<2+>敏感性诱导正常肺动脉血管收缩；(5) PAR4的激活诱导内皮细胞产生NO的方式不依赖于Ca^<2+>信号，依赖于磷脂酰肌醇3-激酶/Akt通路。少