YAP1/TEAD1 upregulate platelet-derived growth factor receptor beta to promote vascular smooth muscle cell proliferation and neointima formation.
YAP1/TEAD1 upregulate platelet-derived growth factor receptor beta to promote vascular smooth muscle cell proliferation and neointima formation.
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DOI：
10.1016/j.yjmcc.2021.03.005
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发表时间：
2021-07
影响因子：
5
通讯作者：
Zhou J
中科院分区：
文献类型：
--
作者：
Osman I;Dong K;Kang X;Yu L;Xu F;Ahmed ASI;He X;Shen J;Hu G;Zhang W;Zhou J
我们之前已经证明转录辅助因子 yes 相关蛋白 1 (YAP1) 促进血管平滑肌细胞 (VSMC) 去分化。然而，YAP1 在体内新内膜形成中的作用和潜在机制仍不清楚。本研究的目的是调查 VSMC 表达的 YAP1 在血管损伤诱导的 VSMC 增殖中的作用，并阐明其作用机制。利用 YAP1 功能获得或丧失的实验表明，YAP1 促进人类 VSMC 增殖。从机制上讲，我们将血小板源性生长因子受体β (PDGFRB) 确定为一种新型 YAP1 靶基因，可在 VSMC 中赋予 YAP1 依赖性过度增殖作用。此外，我们确定 TEA 域转录因子 1 (TEAD1) 是介导 YAP1 依赖性 PDGFRβ 表达的关键转录因子。 ChIP 测定表明 TEAD1 在 PDGFRB 基因增强子处富集。荧光素酶报告基因检测进一步证明 YAP1 和 TEAD1 协同激活 PDGFRB 增强子。与这些观察结果一致，我们发现动脉损伤后 YAP1 表达上调，并与体内 PDGFRβ 表达和 VSMC 增殖相关。使用新型诱导型 SM 特异性 Yap1 敲除小鼠模型，我们发现成人 VSMC 中 Yap1 的特异性缺失足以减弱动脉损伤诱导的新内膜形成，这主要是由于 PDGFRβ 表达和 VSMC 增殖受到抑制。我们的研究揭示了一种新机制，YAP1/TEAD1 通过 PDGFRβ 的转录诱导促进 VSMC 增殖，从而增强 PDGF-BB 下游信号传导并促进新内膜形成。
We have previously demonstrated that the transcription co-factor yes-associated protein 1 (YAP1) promotes vascular smooth muscle cell (VSMC) de-differentiation. Yet, the role and underlying mechanisms of YAP1 in neointima formation in vivo remain unclear. The goal of this study was to investigate the role of VSMC-expressed YAP1 in vascular injury-induced VSMC proliferation and delineate the mechanisms underlying its action. Experiments employing gain- or loss-of-function of YAP1 demonstrated that YAP1 promotes human VSMC proliferation. Mechanistically, we identified platelet-derived growth factor receptor beta (PDGFRB) as a novel YAP1 target gene that confers the YAP1-dependent hyper-proliferative effects in VSMCs. Furthermore, we identified TEA domain transcription factor 1 (TEAD1) as a key transcription factor that mediates YAP1-dependent PDGFRβ expression. ChIP assays demonstrated that TEAD1 is enriched at a PDGFRB gene enhancer. Luciferase reporter assays further demonstrated that YAP1 and TEAD1 co-operatively activate the PDGFRB enhancer. Consistent with these observations, we found that YAP1 expression is upregulated after arterial injury and correlates with PDGFRβ expression and VSMC proliferation in vivo. Using a novel inducible SM-specific Yap1 knockout mouse model, we found that the specific deletion of Yap1 in adult VSMCs is sufficient to attenuate arterial injury-induced neointima formation, largely due to inhibited PDGFRβ expression and VSMC proliferation. Our study unravels a novel mechanism by which YAP1/TEAD1 promote VSMC proliferation via transcriptional induction of PDGFRβ, thereby enhancing PDGF-BB downstream signaling and promoting neointima formation.
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影响因子：
64.5
作者：
Dong, Jixin;Feldmann, Georg;Pan, Duojia
通讯作者：
Pan, Duojia
DOI：
10.1161/01.atv.17.10.2238
发表时间：
1997-10-01
影响因子：
8.7
作者：
Kumar, A;Lindner, V
通讯作者：
Lindner, V
影响因子：
5
作者：
Kimura TE;Duggirala A;Smith MC;White S;Sala-Newby GB;Newby AC;Bond M
通讯作者：
Bond M
影响因子：
12.4
作者：
Liu, Jinhua;Wen, Tong;Zhou, Jiliang
通讯作者：
Zhou, Jiliang
影响因子：
8.7
作者：
Panek, RL;Dahring, TK;Keiser, JA
通讯作者：
Keiser, JA