The Neuropilin 1 Cytoplasmic Domain Is Required for VEGF-A-Dependent Arteriogenesis

Neuropilin 1 (NRP1) plays an important but ill-defined role in VEGF-A signaling and vascular morphogenesis. We show that mice with a knockin mutation that ablates the NRP1 cytoplasmic tail (Nrp1cyto) have normal angiogenesis but impaired developmental and adult arteriogenesis. The arteriogenic defect was traced to the absence of a PDZ-dependent interaction between NRP1 and VEGF receptor 2 (VEGFR2) complex and synectin, which delayed trafficking of endocytosed VEGFR2 from Rab5+ to EAA1+ endosomes. This led to increased PTPN1 (PTP1b)-mediated dephosphorylation of VEGFR2 at Y1175, the site involved in activating ERK signaling. The Nrp1cyto mutation also impaired endothelial tubulogenesis in vitro, which could be rescued by expressing full-length NRP1 or constitutively active ERK. These results demonstrate that the NRP1 cytoplasmic domain promotes VEGFR2 trafficking in a PDZ-dependent manner to regulate arteriogenic ERK signaling and establish a role for NRP1 in VEGF-A signaling during vascular morphogenesis. [Display omitted] •The NRP1 cytoplasmic domain promotes VEGF receptor (VEGFR) 2 endocytic trafficking•In its absence, VEGR2 trafficking is delayed in sorting endosomes•PTP1b binds to Rab5+ sorting endosomes and dephosphorylates the Y1175 site of VEGFR2•Loss of the NRP1 cytoplasmic domain impairs developmental and adult arteriogenesis Lanahan et al. find that the VEGF coreceptor NRP1 is required for proper VEGFR2 endocytic trafficking. In knockin mice lacking NRP1’s cytoplasmic domain, VEGFR2 passes through early endocytic compartments more slowly, increasing its exposure to the inhibitory phosphatase PTP1b and attenuating VEGF-stimulated ERK signaling and arteriogenesis.