YAP and TAZ in Vascular Smooth Muscle Confer Protection Against Hypertensive Vasculopathy.
YAP and TAZ in Vascular Smooth Muscle Confer Protection Against Hypertensive Vasculopathy.
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DOI：
10.1161/atvbaha.121.317365
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发表时间：
2022-04
期刊：
影响因子：
--
通讯作者：
Albinsson S
中科院分区：
文献类型：
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作者：
Daoud F;Arévalo Martinez M;Holmberg J;Alajbegovic A;Ali N;Rippe C;Swärd K;Albinsson S
高血压仍然是心血管疾病的主要危险因素，但其潜在的机制尚不清楚。我们假设，适当的机械转导和血管平滑肌细胞的收缩功能是维持血管壁完整性的关键。河马途径效应因子YAP(YES-Associated Protein 1)和TAZ(包含转录调节因子1的WW结构域)已被鉴定为机械敏感性转录共激活因子。然而，它们在血管平滑肌细胞机械转导中的作用还没有在体内进行研究。我们利用可诱导的YAP/TAZ基因敲除小鼠模型进行了生理和分子分析。缺乏YAP/TAZ的动脉减少了激动剂介导的收缩，降低了肌源性反应，并减弱了拉伸诱导的平滑肌标志物的转录调节。此外，在已建立的高血压中，YAP/TAZ基因敲除会导致肠系膜小动脉的严重血管病变，其特征是新生内膜增生、弹性蛋白降解和外膜增厚。本研究证实了YAP/TAZ对高血压血管病变的保护作用。
Hypertension remains a major risk factor for cardiovascular diseases, but the underlying mechanisms are not well understood. We hypothesize that appropriate mechanotransduction and contractile function in vascular smooth muscle cells are crucial to maintain vascular wall integrity. The Hippo pathway effectors YAP (yes-associated protein 1) and TAZ (WW domain containing transcription regulator 1) have been identified as mechanosensitive transcriptional coactivators. However, their role in vascular smooth muscle cell mechanotransduction has not been investigated in vivo. We performed physiological and molecular analyses utilizing an inducible smooth muscle–specific YAP/TAZ knockout mouse model. Arteries lacking YAP/TAZ have reduced agonist-mediated contraction, decreased myogenic response, and attenuated stretch-induced transcriptional regulation of smooth muscle markers. Moreover, in established hypertension, YAP/TAZ knockout results in severe vascular lesions in small mesenteric arteries characterized by neointimal hyperplasia, elastin degradation, and adventitial thickening. This study demonstrates a protective role of YAP/TAZ against hypertensive vasculopathy.