Jia, M.; Zhuo, J.; Zhao, X.; Liu, T.; Zhang, H.; Xu, K.; Wang, P.; Xu, C.

Vascular smooth muscle cell (VSMC) phenotypic switching from a contractile to syn-thetic state plays a pivotal role in vascular remodeling. Although genome-wide associ-ation studies have linked NINJ2 (encode Ninjurin2) polymorphisms are associated with risk of atherosclerosis and related conditions like ischemic stroke and coronary artery disease, its functional role in regulating VSMC plasticity remains unexplored. Here, using Ninj2 knockout (Ninj2-/-) and smooth muscle-specific overexpressing (Ninj2smcTG) mice subjected to carotid artery ligation, we demonstrate that Ninjurin2 deficiency exacerbates injury-induced intimal hyperplasia, whereas its overexpression attenuates this pathological remodeling. Mechanistically, Ninjurin2 knockdown pro-moted PDGF-BB-mediated VSMC phenotypic switching, proliferation, and migration, while biochemical studies revealed that Ninjurin2 interacts with PDGFR{beta} to suppress FAK signaling. These findings identify Ninjurin2 as a novel regulator of VSMC pheno-typic switching via the PDGFR{beta}/FAK axis, offering new mechanistic insights into vas-cular remodeling and potential therapeutic avenues for atherosclerosis.