The Hippo signaling pathway is involved in the pathophysiology of various cardiovascular diseases. Yes-associated protein (YAP) and transcriptional enhancer activator domain (TEAD) transcriptional factors, the main transcriptional complex of the Hippo pathway, were recently identified as modulators of phenotypic switching of vascular smooth muscle cells (VSMCs). However, the intrinsic regulator of YAP/TEAD-mediated gene expressions involved in vascular pathophysiology remains to be elucidated. Here, we identified Homeobox A4 (HOXA4) as a potent repressor of YAP/TEAD transcriptional activity using lentiviral shRNA screen. Mechanistically, HOXA4 interacts with TEADs and attenuates YAP/TEAD-mediated transcription by competing with YAP for TEAD binding. We also clarified that the expression of HOXA4 is relatively abundant in the vasculature, especially in VSMCs. In vitro experiments in human VSMCs showed HOXA4 maintains the differentiation state of VSMCs via inhibition of YAP/TEAD-induced phenotypic switching. We generated Hoxa4-deficient mice and confirmed the downregulation of smooth muscle-specific contractile genes and the exacerbation of vascular remodeling after carotid artery ligation in vivo. Our results demonstrate that HOXA4 is a repressor of VSMC phenotypic switching by inhibiting YAP/TEAD-mediated transcription.

中文翻译：

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Homeobox A4 通过抑制 YAP/TEAD 转录活性来抑制血管重塑。

Hippo信号通路参与多种心血管疾病的病理生理学。Yes 相关蛋白 (YAP) 和转录增强子激活结构域 (TEAD) 转录因子是 Hippo 通路的主要转录复合物，最近被确定为血管平滑肌细胞 (VSMC) 表型转换的调节剂。然而，参与血管病理生理学的 YAP/TEAD 介导的基因表达的内在调节因子仍有待阐明。在这里，我们使用慢病毒 shRNA 筛选将 Homeobox A4 (HOXA4) 鉴定为 YAP/TEAD 转录活性的有效抑制因子。从机制上讲，HOXA4 与 TEAD 相互作用并通过与 YAP 竞争 TEAD 结合来减弱 YAP/TEAD 介导的转录。我们还澄清了 HOXA4 在脉管系统中的表达相对丰富，特别是在 VSMC 中。人类 VSMC 的体外实验表明 HOXA4 通过抑制 YAP/TEAD 诱导的表型转换来维持 VSMC 的分化状态。我们生成了 Hoxa4 缺陷小鼠，并证实了体内颈动脉结扎后平滑肌特异性收缩基因的下调和血管重塑的加剧。我们的结果表明 HOXA4 通过抑制 YAP/TEAD 介导的转录来抑制 VSMC 表型转换。