前列腺素E2受体EP4在肺动脉高压中的作用及机制研究

肺动脉高压是一种高致残率和致死率的疾病，然而目前因对其发病机制研究不够深入，临床治疗肺动脉高压的药物和方法均为对症治疗，效果十分有限。肺动脉血管张力和血管重塑是其病理基础，由此为切入点进一步阐明肺动脉高压的发病机制势在必行。有证据表明，前列腺素E2受体EP4与肺动脉高压的发病关系密切，我们前期工作表明血管平滑肌细胞EP4参与调控肺动脉张力并参与主动脉血管重构。我们提出假说：血管平滑肌细胞EP4通过调控血管张力和血管重构参与肺动脉高压发病过程。我们将主要利用EP4基因半敲小鼠、血管平滑肌细胞EP4受体特异性敲除和过表达小鼠构建肺动脉高压模型，结合离体血管环实验和细胞及分子生物学实验，探讨EP4在肺动脉高压发病中对血管舒张功能和细胞的作用及其分子机制。本课题的开展将有助于阐明EP4在肺动脉高压的作用，从而为基于EP4的治疗肺动脉高压的药物开发提供靶点。

Pulmonary.artery hypertension (PAH) is a severe and fatal progressive disease, characterized by increased pulmonary vascular resistance leading to right heart failure and death. The effectiveness of anti-PAH drugs or methods, which are only symptomatic treatment, is limited. Both pulmonary artery tone and vascular remodeling are important pathological factors of PAH. It is urgent to elucidate the pathogenesis mechanism and provide more drug targets for treating PAH. There is evidence that prostaglandin E2 receptor EP4 is closely related to the pathogenesis of PAH. Our previous work shows that vascular smooth muscle cell EP4 (VSMC-EP4) is involved in regulating pulmonary artery tension and aortic vascular remodeling. Therefore, we hypothesize is that VSMC-EP4 participates in the pathogenesis of pulmonary hypertension by regulating vascular tension and vascular remodeling. We will use EP4 gene hemi-deficient mice, VSMC specific EP4 receptor knockout mice and overexpression mice to induce PAH mouse model. Combine with ex vivo arterial ring and cell and molecular biology experiments, we will explore the role of EP4 in vascular relaxation and cellular function and its underlying molecular mechanism in the pathogenesis of PAH. The completion of the present project will help to clarify the role of EP4 in PAH, thus providing a target for drug development based on EP4 for the treatment of PAH.