ZHX2 Alleviates Vascular Remodeling and Smooth Muscle Cell Proliferation by Transcriptional Regulation of GADD45G.

Based on findings from human atherosclerotic arteries and mouse arterial injury models, where ZHX2 expression is significantly downregulated, this study identifies ZHX2 as a critical inhibitor of pathological vascular remodeling. Functionally, local adenoviral overexpression of ZHX2 in vivo attenuates neointima formation in a mouse carotid artery ligation model, while in vitro experiments demonstrate that ZHX2 impedes the proliferation and migration of primary Vascular Smooth Muscle Cells (VSMCs). Mechanistically, integrated RNA-seq and ChIP-seq analyses reveal that ZHX2 transcriptionally regulates GADD45G, directly binding to its promoter and activating its transcription. The essential role of this pathway is confirmed by the finding that knockdown of GADD45G counteracts the inhibitory effects of ZHX2 overexpression on VSMC proliferation, migration, and neointima formation. Consequently, the ZHX2/GADD45G signaling axis is highlighted as a potential regulatory pathway in injury-associated neointimal remodeling.