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Neuropilin-1 mediates vascular permeability independently of vascular endothelial growth factor receptor-2 activation

Roth, L; Prahst, C; Ruckdeschel, T; Savant, S; Westrom, S; Fantin, A; Riedel, M; ... Augustin, HG; + view all (2016) Neuropilin-1 mediates vascular permeability independently of vascular endothelial growth factor receptor-2 activation. Science Signaling , 9 (425) , Article ra42. 10.1126/scisignal.aad3812. Green open access

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Abstract

Neuropilin-1 (NRP1) regulates developmental and pathological angiogenesis, arteriogenesis, and vascular permeability, acting as a coreceptor for semaphorin 3A (Sema3A) and the 165–amino acid isoform of vascular endothelial growth factor A (VEGF-A165). NRP1 is also the receptor for the CendR peptides, a class of cell- and tissue-penetrating peptides with a specific R-x-x-R carboxyl-terminal motif. Because the cytoplasmic domain of NRP1 lacks catalytic activity, NRP1 is mainly thought to act through the recruitment and binding to other receptors. We report here that the NRP1 intracellular domain mediates vascular permeability. Stimulation with VEGF-A165, a ligand-blocking antibody, and a CendR peptide led to NRP1 accumulation at cell-cell contacts in endothelial cell monolayers, increased cellular permeability in vitro and vascular leakage in vivo. Biochemical analyses, VEGF receptor-2 (VEGFR-2) silencing, and the use of a specific VEGFR blocker established that the effects induced by the CendR peptide and the antibody were independent of VEGFR-2. Moreover, leakage assays in mice expressing a mutant NRP1 lacking the cytoplasmic domain revealed that this domain was required for NRP1-induced vascular permeability in vivo. Hence, these data define a vascular permeability pathway mediated by NRP1 but independent of VEGFR-2 activation.

Type: Article
Title: Neuropilin-1 mediates vascular permeability independently of vascular endothelial growth factor receptor-2 activation
Open access status: An open access version is available from UCL Discovery
DOI: 10.1126/scisignal.aad3812
Publisher version: http://dx.doi.org/10.1126/scisignal.aad3812
Language: English
Additional information: This is the author's version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Signaling {9(425), 26 April 2016}, doi: 10.1126/scisignal.aad3812.
Keywords: science & technology, life sciences & biomedicine, biochemistry & molecular biology, cell biology, in-vivo, transmembrane domain, structural basis, nervous-system, semaphorin-iii, tumor-cells, factor VEGF, SRC kinase, binding, angiogenesis
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/1489835
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