前列腺素E2受体EP4在血管稳态维持及重塑中的作用

Vascular homeostasis is essential for healthy life. Disruption of vascular homeostasis is the common pathophysilogical basis for a variety of cardiovascular diseases associated with functional and structural vascular remodeling, including hypertension, aortic aneurysm, and vascular restenosis after percutaneous transluminal coronary angioplasty (PTCA).However, the underlying mechanisms involved in the maintenance of vascular homeostasis and the pathogenesis of vascular remodeling remain largely unknown. Increasing evidence demonstrates that prostaglandin E2 (PGE2), a major cyclooxygenase metabolite of arachidonic acid produced in the vasculature, plays an important role in regulating vascular function and integrity.PGE2 exerts its biological function via four membrane-associated G protein-coupled receptors, designated EP1, EP2, EP3 and EP4. Our preliminary studies provide strong evidence that EP4 is critical for maintaining vascular homeostasis. The present studies are aimed to investigate the role of vascular EP4 in the regulation of vascular function and in the pathogenesis of hypertension, aortic aneurysm, and vascular restenosis. We will also evaluate the possibility that EP4 may represent a novel therapeutic target for the treatment of cardiovascular disorders associated with vascular remodeling. The EP4 gene hemi-deficient mice, vascular endothelial cell (EC)- and smooth muscle cell (VSMC)-specific EP4 transgenic mice, EC- and VSMC-specific EP4 gene knockout mice, EP4 selective agonists and antagonists will be utilized to determine whether dysfunction of EP4 contributes to the development of these cardiovascular diseases. In vitro studies on cultured ECs and VSMCs will be performed to define the underlying molecular mechanisms. The completion of the present studies could help clarify the role of EP4 in vascular homeostasis and the pathogenesis of hypertension, aortic aneurysm and restenosis. The findings may lead to new strategies for effective prevention and treatment for these severe cardiovascular disorders.

血管稳态失衡导致的血管功能性和结构性重构是包括高血压、主动脉瘤及血管再狭窄等重大心血管疾病的病生理基础。然而，迄今为止血管稳态维持及血管重塑发生的机制远未阐明。大量证据表明血管组织中花生四烯酸环氧酶代谢的主要产物--前列腺素E2（PGE2）在调节血管功能及正常结构中发挥重要作用。PGE2 通过EP1、EP2、EP3 和EP4四种受体介导其生物学功能。我们前期的研究发现EP4受体可能与血管稳态维持有重要关系。本课题旨在揭示EP4受体在血管调节及血管重塑性疾病发生中的作用。我们将运用EP4基因半缺失小鼠、血管内皮细胞和血管平滑肌细胞EP4受体组织特异性转基因和基因敲除小鼠，探讨EP4受体在高血压、主动脉瘤及血管再狭窄等血管重塑性疾病发生发展中的作用，并揭示其机制。本课题的开展将有助于阐明EP4受体在血管稳态调节中的作用，从而为评估EP4受体作为重要血管重塑性疾病治疗靶点的可能性提供实验依据。

血管稳态失衡导致的血管功能性和结构性重构是包括高血压、主动脉瘤及血管再狭窄等重 大心血管疾病的病生理基础，也是这些重大血管疾病干预的重要靶点。然而，迄今为止血管稳态维持及血管重塑发生的机制远未阐明。本项目旨在揭示花生四烯酸，一种n-6长链不饱和脂肪酸，环氧酶代谢产物-前列腺素E2 及其EP4受体在血管调节及血管重塑性疾病发生中的作用。本项目运用全身、血管内皮细胞和血管平滑肌细胞EP4受体组织特异性转基因和基因敲除小鼠，以及EP4特异性激动剂、拮抗剂和EP4过表达腺病毒等实验材料，深入探讨了EP4受体在高血压、主动脉瘤及血管再狭窄等疾病发生、发展中的作用，并揭示其作用机制。本项目的研究成果主要包括：1）建立了世界领先的用于研究PGE2-EP4信号轴的研究平台，特别是组织特异性转基因和基因敲除小鼠品系； 2）首次发现并证实PGE2-EP4信号轴在维持正常血压和高血压发生中的核心作用，并在临床前模式动物上初步验证了基于EP4受体激动的干预手段在高血压治疗中的疗效，可望为高血压临床治疗提供一种新的防治策略；3）率先揭示了PGE2-EP4信号轴功能缺陷在主动脉夹层发生、发展中的作用，为该临床凶险血管疾病的治疗提供了新的靶点；4）初步明确了PGE2-EP4信号轴在动脉再狭窄发生中的促进作用，为其防治提供了新的线索； 5）建立了一种不依赖高脂血症（ApoE-/-或LDLR-/-）的主动脉夹层动物模型，提示血脂代谢紊乱并非主动脉夹层发生所必须。本课题的开展不仅阐明了EP4受体在血管稳态调节中的重要作用，也为评估EP4受体作为重要血管重塑性疾病治疗靶点的可能性提供了实验依据。