Neuropilin-1 controls vascular permeability through juxtacrine regulation of endothelial adherens junctions

Abstract

Neuropilin-1 (NRP1) regulates endothelial cell (EC) biology through modulating vascular endothelial growth factor receptor 2 (VEGFR2) signalling by presenting VEGFA. How NRP1 impacts VEGFA-mediated vascular hyperpermeability however is unresolved, being described as having a positive or passive function. Using EC-specific Nrp1 knock-out mice, we discover that EC-expressed NRP1 exerts an organotypic role. In ear skin, VEGFA/VEGFR2-mediated vascular leakage increased following EC NRP1 knock-out, showing that NRP1 negatively regulates VEGFR2 signalling. Conversely, in back skin and trachea, EC NRP1 knock-out decreased vascular leakage. Accordingly, VE-cadherin phosphorylation increased in the ear skin but was suppressed in back skin of Nrp1 iECKO mice. NRP1 has been shown to have the ability to act in a juxtacrine manner. Importantly, NRP1 was more abundant in perivascular cells of the ear skin than back skin. Global NRP1 knock-out suppressed VEGFA-induced vascular leakage in the ear skin, implicating perivascular NRP1 as a juxtacrine co-receptor of VEGFA in this compartment. Altogether, we demonstrate that perivascular NRP1 is an active participant in EC VEGFA/VEGFR2 signalling and acts as an organotypic modifier of EC biology.