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

血栓形成在各种血管疾病的发病机制和病理生理学中起着关键作用。蛋白酶，如凝血酶，激活蛋白酶激活受体（PAR），从而发挥血管效应，包括血管收缩、平滑肌增殖、血管通透性过高和产生内皮衍生的血管活性物质。然而，PAR在血管疾病的发病机制和病理生理学中的作用仍有待阐明。在本研究中，我们推进了我们的早期研究的生理作用的PARs在调节血管功能，从而调查的病理生理作用的PARs在血管疾病。特别是，我们把我们的特别注意力集中在血管张力和增殖的调节，这在血管疾病的病理生理学中起着核心作用。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PAR 1在血管痉挛反应中的作用。 关于我们 蛛网膜下腔出血的出血性血管痉挛;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PAR表达的变化、对PAR激动剂的反应以及信号转导机制。我们还研究了PAR 1和PAR 4介导的内皮NO产生的分子机制。因此，我们首次阐明了：（1）Rac 1通过激活膜运输调节PAR 1的细胞表面表达;（2）球囊损伤上调了PAR 1和PAR 2的表达，从而增强了对凝血酶和胰蛋白酶的收缩反应;（3）凝血酶诱导了PAR 1的上调和对凝血酶的收缩反应的增强;（4）凝血酶通过升高[Ca^<2+>]_i和收缩器官的Ca^<2+>敏感性引起正常肺动脉收缩：（5）PAR 4的激活不依赖于Ca^<2+>信号，而依赖于磷脂酰肌醇3-激酶/Akt途径诱导内皮细胞NO的产生。少

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