PAI-1及其糖基化玻连蛋白在糖尿病血管重构的作用和机制

Vascular remodeling plays a key role in the regulation of diabetic vascular complication. PAI-1 and its bind vitronectin (VN), are strongly associated with diabetic microangiopathy. However, the mechanisms are still unknown. Our preliminary results indicated that VEGF binds VN, and the glycation of VN showed a conformational change. Furthermore, PAI-1 inhibts VEGF-induced VEGFR-2 phosphorylation in human endothelial cell, and PDGF-BB-induced migration of vascular smooth muscle cells. Inhibition of PAI-1 increased the blood perfusion in a mouse diabetic hindlimb ischemia model, suggesting PAI-1/AGE-VN might play a role in the regulation of vascular remodeling. Based on these findings, we hypothesize the following aims: 1) Determine the basic structure and function of glycated VN; 2) Define the regulation of PAI-1/AGE-VN in VEGF and PDGF-BB signaling in vitro; 3) Study the role of PAI-1/AGE-VN in the regulation of angiogenesis and vascular remodeling in diabetic mice model and knockout mice. We anticipate that the proposed studies will lead to the development of new strategies to control angiogenesis and vascular remodeling in diabetic microangiopathy.

血管重构是糖尿病血管病变的始动环节及病理生理基础。研究显示糖尿病血管病变与PAI-1及其结合玻连蛋白（VN）密切相关，糖基化VN (AGE-VN) 对糖尿病血管重构的作用目前还不清楚。最近我们发现VEGF与VN结合，糖基化改变VN蛋白构造，显示AGE-VN可能影响血管生长因子功能。进一步发现PAI-1抑制内皮细胞VEGFR-2磷酸化和血管平滑肌细胞迁移。在糖尿病下肢缺血小鼠模型，抑制PAI-1增加缺血区血流灌注，提示PAI-1/AGE-VN可能参与血管重构。为证实该假设，本项目以血管内皮细胞与血管壁细胞及其连接为切入点，查明：1) 确定AGE-VN的基本结构和功能；2) PAI-1/ AGE-VN对VEGF和PDGF-BB信号通路及血管细胞功能的调节；3) 应用糖尿病模型和基因敲除鼠，研究PAI-1/AGE-VN调节糖尿病血管形成与血管重构的机理。为治疗糖尿病血管病变提供新的治疗靶点。

血管重构是糖尿病血管病变的始动环节及病理生理基础。PAI-1显示了在新生血管形成中对内皮细胞和血管稳定性的影响。研究显示糖尿病血管病变与PAI-1及其结合玻连蛋白（VN）密切相关，糖基化VN (AGE-VN) 对糖尿病血管重构的作用目前还不清楚。最近我们发现VEGF与VN结合，糖基化改变VN蛋白构造，显示AGE-VN可能影响血管生长因子功能。进一步发现PAI-1抑制内皮细胞VEGFR-2磷酸化和血管平滑肌细胞迁移。我们以血管内皮细胞与血管壁细胞及其连接为切入点，查明：1) PAI-1/ VN对VEGF和PDGF-BB信号通路及血管细胞功能的调节；2) 研究血管壁细胞间相互作用对糖尿病血管重构的机理； 3）应用糖尿病模型和基因敲除鼠，研究PAI-1调节糖尿病脂肪炎症与葡萄糖代谢的调节机理。我们还发现了PAI-1调节糖尿病白色脂肪组织炎症极性和葡萄糖稳态，这个新的发现有望从脂肪组织研究PAI-1调节葡萄糖稳态和胰岛素抵抗，进一步发现治疗糖尿病的新方法。这是一个新的研究课题，国内外尚未见报道。阐明PAI-1对血管形成和血管稳定性的调节机制，为治疗糖尿病血管病变提供新的治疗靶点。