MCC links Wnt/PCP signaling to endothelial polarity and vascular remodeling

Abstract

Vascular remodeling is crucial for establishing a functional vasculature and maintaining organ homeostasis. In the central nervous system (CNS), Wnt signaling plays a critical role in guiding endothelial cell (EC) behavior during vascular development and specialization. While canonical Wnt/β-catenin signaling regulates endothelial specification and blood–brain barrier formation, the non-canonical Wnt/Planar Cell Polarity (PCP) pathway orchestrates vascular remodeling and flow adaptation. However, how PCP signaling is transduced into intracellular polarity control remains unknown. Here, we identify MCC (Mutated in Colorectal Cancer) as a key regulator of endothelial polarity and migration downstream of the Wnt/PCP signaling pathway. Mechanistically, MCC interacts with the centriolar satellite protein CEP131 and promotes its turnover through proteasome- and autophagy-dependent pathways, thereby maintaining centrosome-associated organization required for directional polarity. MCC depletion disrupts directional polarity while preserving and enhancing flow-induced cytoskeletal elongation, revealing a functional dissociation between alignment and front–rear polarization. In vivo, endothelial-specific deletion of Mcc in the postnatal retina impairs vascular remodeling, reduces endothelial proliferation, and disrupts polarity at the angiogenic front. Notably, normalization of vascular density and regression by captopril does not restore polarity, indicating a cell-intrinsic role for MCC in endothelial organization. Together, these findings uncover an MCC–CEP131 axis linking Wnt/PCP signaling to centrosome-associated proteostasis and identify MCC as a key coordinator of endothelial polarity during vascular remodeling.