P197Neuropilin (NRP) 1 hypomorphism combined with defective VEGF-A binding reveals novel roles for NRP1 in developmental and pathological angiogenesis

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Purpose: Neuropilin 1 (NRP1) is a receptor for class 3 semaphorins and vascular endothelial growth factor A (VEGF) and essential for cardiovascular development. Biochemical evidence supports a model for NRP1 function in which VEGF binding induces complex formation between NRP1 and VEGFR2 to enhance endothelial VEGF signalling. However, the relevance of VEGF binding to NRP1 for angiogenesis in vivo is unclear. We therefore generated knock-in mice expressing Nrp1 with a mutation of tyrosine (Y) 297 in the VEGF binding pocket of the NRP1 b1 domain, a residue previously shown to be important for high affinity VEGF binding and NRP1/VEGFR2 complex formation.

Methods: Homozygous NRP1Y297A/Y297A knock-in mice and mouse phenotyping were performed using established previously published methods.

Results: Unexpectedly, this targeting strategy also reduced NRP1 expression and therefore generated a NRP1 hypomorph. Despite the loss of VEGF binding and attenuated NRP1 expression, homozygous Nrp1Y297A/Y297A mice were born at normal Mendelian ratios, arguing against NRP1 functioning exclusively as a VEGF164 receptor in embryonic angiogenesis. By overcoming the mid-gestation lethality of full Nrp1-null mice, homozygous Nrp1Y297A/Y297A mice further revealed essential roles for NRP1 in postnatal angiogenesis and arteriogenesis in the heart and retina, pathological neovascularisation of the retina and angiogenesis-dependent tumour growth.

Conclusions: The mild embryonic vascular phenotypes combined with the extended viability of Nrp1Y297A/Y297A relative to full and endothelial-specific NRP1 knockout mice clearly demonstrates for the first time that VEGF-binding to NRP1 is not essential for embryonic angiogenesis and therefore that NRP1 functions in embryonic EC predominantly in a VEGF-independent role.

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