Neuropilin 1 regulates angiogenesis in a VEGF-independent manner via association with ABL1, suggesting that Imatinib represents a novel opportunity for anti-angiogenic therapy.

Fantin et al. show that the VEGF isoform VEGF165 signals through a complex of VEGFR2 and NRP1, in which the NRP1 cytoplasmic domain promotes the ABL-mediated activation of SRC family kinases to evoke a hyperpermeability response, a known cause of pathological edema.

SummarySprouting blood vessels are led by filopodia-studded endothelial tip cells that respond to angiogenic signals. Mosaic lineage tracing previously revealed that NRP1 is essential for tip cell function, although its mechanistic role in tip cells remains poorly defined. Here, we show that NRP1 is dispensable for genetic tip cell identity. Instead, we find that NRP1 is essential to form the filopodial bursts that distinguish tip cells morphologically from neighboring stalk cells, because it enables the extracellular matrix (ECM)-induced activation of CDC42, a key regulator of filopodia formation. Accordingly, NRP1 knockdown and pharmacological CDC42 inhibition similarly impaired filopodia formation in vitro and in developing zebrafish in vivo. During mouse retinal angiogenesis, CDC42 inhibition impaired tip cell and vascular network formation, causing defects that resembled those due to loss of ECM-induced, but not VEGF-induced, NRP1 signaling. We conclude that NRP1 enables ECM-induced filopodia formation for tip cell function during sprouting angiogenesis.

Blood vessel formation during vertebrate development relies on a process called angiogenesis and is essential for organ growth and tissue viability. In addition, angiogenesis leads to pathological blood vessel growth in diseases with tissue ischaemia, such as neovascular eye disease and cancer. Neuropilin 1 (NRP1) is a transmembrane protein that serves as a receptor for the VEGF₁₆₅ isoform of the vascular endothelial growth factor (VEGF) to enhance cell migration during angiogenesis via VEGF receptor 2 (VEGFR2), and it is also essential for VEGF-induced vascular permeability and arteriogenesis. In addition, NRP1 activation affects angiogenesis independently of VEGF signalling by activating the intracellular kinase ABL1. NRP1 also acts as a receptor for the class 3 semaphorin (SEMA3A) to regulate vessel maturation during tumour angiogenesis and vascular permeability in eye disease. In the present paper, we review current knowledge of NRP1 regulation during angiogenesis and vascular pathology.

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