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Homeobox A4 suppresses vascular remodeling by repressing YAP / TEAD transcriptional activity
Author(s) -
Kimura Masahiro,
Horie Takahiro,
Baba Osamu,
Ide Yuya,
Tsuji Shuhei,
Ruiz Rodriguez Randolph,
Watanabe Toshimitsu,
Yamasaki Tomohiro,
Otani Chiharu,
Xu Sijia,
Miyasaka Yui,
Nakashima Yasuhiro,
Kimura Takeshi,
Ono Koh
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201948389
Subject(s) - repressor , vascular smooth muscle , microbiology and biotechnology , hippo signaling pathway , transcription factor , biology , homeobox , enhancer , downregulation and upregulation , neointima , transcription (linguistics) , signal transduction , gene , genetics , medicine , endocrinology , restenosis , linguistics , philosophy , smooth muscle , stent
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 ( VSMC s). However, the intrinsic regulator of YAP / TEAD ‐mediated gene expressions involved in vascular pathophysiology remains to be elucidated. Here, we identified Homeobox A4 ( HOXA 4) as a potent repressor of YAP / TEAD transcriptional activity using lentiviral sh RNA screen. Mechanistically, HOXA 4 interacts with TEAD s and attenuates YAP / TEAD ‐mediated transcription by competing with YAP for TEAD binding. We also clarified that the expression of HOXA 4 is relatively abundant in the vasculature, especially in VSMC s. In vitro experiments in human VSMC s showed HOXA 4 maintains the differentiation state of VSMC s 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 HOXA 4 is a repressor of VSMC phenotypic switching by inhibiting YAP / TEAD ‐mediated transcription.