EP3 Receptor Deficiency Improves Vascular Remodeling and Cognitive Impairment in Cerebral Small Vessel Disease.
EP3 Receptor Deficiency Improves Vascular Remodeling and Cognitive Impairment in Cerebral Small Vessel Disease.
复制标题
EP3 受体缺陷可改善脑小血管疾病的血管重塑和认知障碍
DOI：
10.14336/ad.2021.0627
复制
发表时间：
2022-03
影响因子：
7.4
通讯作者：
Fu J
中科院分区：
文献类型：
--
作者：
Liu N;Tang J;Xue Y;Mok V;Zhang M;Ren X;Wang Y;Fu J
年龄和高血压是脑小血管病（CSVD）的主要危险因素。抗高血压治疗已取得有效;然而，治疗CSVD的结果不完整，表明需要额外的治疗。靶向异常炎症反应已成为研究兴趣的主题。小动脉重构是CSVD的主要病理特征。抑制E-前列腺素3（EP 3）受体已被证明可以减弱外周器官的血管重塑;然而，对其在CSVD中的作用知之甚少。因此，我们研究是否缺失EP 3减弱CSVD的发展，在动物模型-中风倾向肾血管性高血压大鼠（RHRsp）。我们发现，RHRsp的大脑小动脉表现出增加的EP 3表达。尽管没有缓解高血压，EP 3的缺失仍然减弱了RHRsp的脑小动脉重塑，如通过减少血管中细胞外基质（ECM）的过度表达所证明的。体外实验表明，EP 3基因缺失可通过下调TGF-β1/Smad信号通路来调控ECM的表达。此外，Morris水迷宫测试和磁共振测试表明，EP 3敲除可能通过增加脑血流量来减轻RHRsp的认知障碍。总之，我们的结果表明，EP 3的缺失可以减轻高血压引起的血管重塑和血管认知障碍，并且EP 3受体的阻断可能是治疗CSVD的一种有希望的策略。
Aging and hypertension are major risk factors for cerebral small vessel disease (CSVD). Anti-hypertensive therapy has achieved effective; however, incomplete results in treating CSVD, suggesting the need for additional treatments. Targeting abnormal inflammatory responses has become a topic of research interest. Small artery remodeling is the main pathological feature of CSVD. Inhibition of the E-prostanoid 3 (EP3) receptor has been shown to attenuate vascular remodeling in peripheral organs; however, little is known about its role in CSVD. Therefore, we investigated whether the deletion of EP3 attenuates the development of CSVD in an animal model-- stroke-prone renovascular hypertensive rat (RHRsp). We found that the cerebral small arteries of RHRsp exhibited increased EP3 expression. Despite no alleviation of hypertension, the deletion of EP3 still attenuated the cerebral small artery remodeling of RHRsp, as evidenced by reduced overexpression of extracellular matrix (ECM) in the vessel. In vitro experiments indicated that EP3 deletion regulated the expression of ECM by downregulating TGF-β1/Smad signaling. Furthermore, the Morris water maze test and magnetic resonance test demonstrated that EP3 knockout attenuated cognitive impairment of the RHRsp, possibly through increased cerebral blood flow. Together, our results indicate that the deletion of EP3 attenuates vascular remodeling and vascular cognitive impairment induced by hypertension, and blockade of the EP3 receptor may be a promising strategy for the treatment of CSVD.