脑小血管病是脑卒中的主要病因，且与卒中复发、认知损害等密切相关，小动脉硬化型是其最主要类型。该病发病机制未完全明了，疗效不佳。慢性炎症介导的血管壁结构改变很可能参与了脑小血管病发病机制。我们发现药物特异性抑制环氧合酶2及其下游前列腺素E2受体EP3可减轻模型鼠脑小血管管壁细胞外基质沉积。敲除小鼠脑微血管平滑肌细胞EP3受体，其合成I型胶原蛋白、纤连蛋白、p-smad2/3减少。本项目首先在EP3敲除SD大鼠基础上，建立EP3敲除的脑小血管病大鼠模型，通过行为学、功能实验和组织染色观察敲除EP3对脑小血管病是否有保护作用；进一步通过各种技术确证转化生长因子β信号通路在EP3调控脑小血管细胞外基质表达中的关键作用，探究EP3偶联何种G蛋白调控小血管细胞外基质表达；最后，检验EP3抑制剂治疗小血管病的安全性。这项研究有望为脑小血管病寻求有效的治疗靶点。

Cerebral small vessel disease (CSVD) is a main reason causing stroke, and related to stroke recurrence and cognitive impairment. The mechanism of CSVD remains unclear and there is little effective treatment. Cerebral small vascular structure changing mediated by chronic inflammation may cause to CSVD. We found that pharmaceutically inhibiting cyclooxygenase 2 (COX-2) or blocking EP3 which is a type of receptor of prostaglandin E2 (PGE2), a product of COX-2, could relieve the accumulation of extracellular matrix in cerebral small vascular wall in spontaneously hypertensive stroke - prone rats (SHRsp), a model of CSVD. And the expression of collagen I, fibronectin and P-Smad2/3 in the cerebral arteriole smooth muscle cell（CASMC）from EP3 knockout (EP3 KO) mice was lower compared with that from wild type mice. In this project, first, we will built an EP3 KO CSVD rat model on the base of EP3 KO SD rat, and confirm whether EP3 KO can relieve CSVD by rat behavior and function study and pathological staining. Second, we will explore whether TGF-β signaling plays a key role on the course of EP3 regulating extracellular matrix (ECM) expression and what type of G protein couple EP3 receptor in this course. Last, we will examine the security and effect of EP3 inhibitor treating for CSVD. Though this project, we may find potential target for the therapy of CSVD.