MT4-MMP-mediated NRP1 shedding fine-tunes VEGFA signaling dynamics during embryonic brain angiogenesis

Angiogenesis is essential for embryonic brain development and tissue repair, yet the mechanisms that spatiotemporally coordinate endothelial behavior to ensure balanced vascular remodeling remain elusive. Here, we identify the glycosylphosphatidylinositol (GPI)-anchored protease MT4-MMP as a critical, context-dependent determinant of angiogenic growth. Global loss of MT4-MMP transiently impairs vascular network formation in the embryonic hindbrain, whereas endothelial-specific deletion triggers an aberrant angiogenesis characterized by increased vessel density, branching, and a profound loss of vascular organization. This dual phenotype reveals MT4-MMP as a fundamental coordinator of neurovascular development. Consistently, MT4-MMP expression was dynamically regulated during wound repair, and its absence amplifies angiogenesis and accelerates wound closure in adult skin, highlighting its role in maintaining vascular homeostasis postnatally. Mechanistically, MT4-MMP-deficient endothelial cells exhibit impaired polarization and sustained, rather than transient, VEGFA-induced ERK activation. We identify NRP1 as a novel substrate of MT4-MMP and demonstrate that MT4-MMP-mediated NRP1 cleavage restricts NRP1 surface availability to tune the intensity of VEGFA signaling. Furthermore, pharmacological blockade of VEGFA–NRP1 binding partially rescues the vascular defects caused by endothelial MT4-MMP loss in vivo . Together, these findings uncover the MT4-MMP/NRP1 axis as a pivotal control point that prevents aberrant vessel expansion, establishing membrane-anchored proteolysis as a primary regulator across developmental and reparative contexts. Teaser The proteolytic constraint exerted by MT4-MMP dictates neurovascular development and wound repair through the spatial control of NRP1-VEGFA signaling.