Neuropilin 2 stabilises adherens junctions and protects against endothelial activation by promoting the interaction between VE cadherin and p120 catenin

Benwell, C.; Ilker, N.; Vaughan, L. B.; Firoglani-Moschi, M.; Price, C.; Mitchell, L.; Liu, T.; Robinson, S. D.

doi:10.1101/2025.03.09.642194

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bioRxiv · 10.1101/2025.03.09.642194

Neuropilin 2 stabilises adherens junctions and protects against endothelial activation by promoting the interaction between VE cadherin and p120 catenin

Benwell, C.·Ilker, N.·Vaughan, L. B.·Firoglani-Moschi, M.·Price, C.·Mitchell, L.·Liu, T.·Robinson, S. D.

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Abstract

The mechanosensing properties of endothelial cell-cell junctions are essential for vascular beds to respond to the mechanical forces exerted by blood flow. In states of disturbed flow, endothelial cells (ECs) become activated and transition to a pro-inflammatory, atheroprone phenotype. Here, we investigated the role of transmembrane glycoprotein neuropilin 2 (NRP2) in maintaining adherens junction integrity using cultured immortalised mouse ECs and a genetically modified mouse model to demonstrate the effects of an endothelial-specific deletion of Nrp2 in vivo. We reveal that, akin to its ortholog, Nrp1, Nrp2 exists as a constituent of adherens junctions, maintaining surface availability of VE cadherin by promoting its interaction with p120 catenin. As a consequence, endothelial knockout mice (Nrp2flfl.ECKO) display hyperpermeable retinal vasculature during development. Nrp2 depletion was subsequently found to activate key pro-inflammatory cytokines and adhesion molecules known to participate in the progression of atherogenesis, in addition to increased immune cell attachment aortic plaque development. These findings describe a role for Nrp2 in maintaining junctional signalling in ECs, protecting against endothelial activation during a state of vascular disease.

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Benwell, C., Ilker, N., Vaughan, L. B., Firoglani-Moschi, M., Price, C., Mitchell, L., Liu, T., Robinson, S. D.. 2025-03-11. Neuropilin 2 stabilises adherens junctions and protects against endothelial activation by promoting the interaction between VE cadherin and p120 catenin. https://doi.org/10.1101/2025.03.09.642194

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