Endothelial major vault protein alleviates vascular remodeling via promoting Parkin-mediated mitophagy.

Jiang, Bin; Bai, Fan; Hu, Yunfu; Ren, Yu; Su, Yuan; Song, Wanxuan; Xie, Kunxin; Wang, Dongdong; Pan, Junlu; Liu, Yuying; Feng, Yuxin; Li, Xiaoyu; Zhang, Hanwen; Zhu, Xudong; Bai, Hui; Yang, Qing; Ben, Jingjing; Chen, Qi

Many important vascular diseases including neointimal hyperplasia and atherosclerosis are characterized by the endothelial cell (EC) injury-initiated pathological vascular remodeling. However, the endogenous regulatory mechanisms underlying it are not fully understood. The present study investigates regulatory role of major vault protein (MVP) in the pathogenesis of vascular remodeling via controlling EC injury. By generating male murine vascular disease models, we find that ablation of endothelial MVP increases neointima formation and promotes atherosclerosis. Mechanistically, MVP directly binds with Parkin and inhibits the ubiquitination and proteasomal degradation of Parkin by dissociating the E3 ligase NEDD4L from Parkin, leading to activation of Parkin-mediated mitophagy pathway in the EC. Genetic modulation of endothelial MVP and Parkin influences the mitophagy, apoptosis, and neointima formation. These results demonstrate that MVP acts as an intracellular regulator promoting Parkin-mediated mitophagy. Our findings suggest that MVP/NEDD4L/Parkin axis may serve as the therapeutic target for treating intimal hyperplasia and atherosclerosis. Endothelial injury drives vascular diseases like atherosclerosis, but key regulators are unclear. Here, the authors show that endothelial major vault protein (MVP) acts as an intracellular regulator promoting Parkin-mediated mitophagy, thereby antagonizing vascular remodeling and suggesting its role as a potential therapeutic target.

UBIQUITIN ligases; VASCULAR remodeling; VASCULAR diseases; PARKIN (Protein); ENDOTHELIAL cells

Nature Communications, 2025, Vol 16, Issue 1, p1

2041-1723

Academic Journal

10.1038/s41467-025-59644-y