title: VEGF165-induced vascular permeability requires NRP1 for ABL-mediated SRC family kinase activation.
abstract: The vascular endothelial growth factor (VEGF) isoform VEGF165 stimulates vascular growth and hyperpermeability. Whereas blood vessel growth is essential to sustain organ health, chronic hyperpermeability causes damaging tissue edema. By combining in vivo and tissue culture models, we show here that VEGF165-induced vascular leakage requires both VEGFR2 and NRP1, including the VEGF164-binding site of NRP1 and the NRP1 cytoplasmic domain (NCD), but not the known NCD interactor GIPC1. In the VEGF165-bound receptor complex, the NCD promotes ABL kinase activation, which in turn is required to activate VEGFR2-recruited SRC family kinases (SFKs). These results elucidate the receptor complex and signaling hierarchy of downstream kinases that transduce the permeability response to VEGF165. In a mouse model with choroidal neovascularisation akin to age-related macular degeneration, NCD loss attenuated vessel leakage without affecting neovascularisation. These findings raise the possibility that targeting NRP1 or its NCD interactors may be a useful therapeutic strategy in neovascular disease to reduce VEGF165-induced edema without compromising vessel growth.
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England, UK c.ruhrberg@ucl.ac.uk a.fantin@ucl.ac.uk.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fantin
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England, UK.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Lampropoulou
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England, UK.
authors.forename: Valentina
authors.initials: V
authors.lastname: Senatore
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England, UK.
authors.forename: James T
authors.initials: JT
authors.lastname: Brash
authors.affiliation: Yale Cardiovascular Research Center, New Haven, CT 06511.
authors.forename: Claudia
authors.identifier: 0000-0002-6412-1907
authors.initials: C
authors.lastname: Prahst
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England, UK.
authors.forename: Clemens A
authors.identifier: 0000-0002-2580-6823
authors.initials: CA
authors.lastname: Lange
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England, UK.
authors.forename: Sidath E
authors.initials: SE
authors.lastname: Liyanage
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England, UK.
authors.forename: Claudio
authors.initials: C
authors.lastname: Raimondi
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England, UK.
authors.forename: James W
authors.initials: JW
authors.lastname: Bainbridge
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany.|Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
authors.forename: Hellmut G
authors.identifier: 0000-0002-7173-4242
authors.initials: HG
authors.lastname: Augustin
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England, UK c.ruhrberg@ucl.ac.uk a.fantin@ucl.ac.uk.
authors.forename: Christiana
authors.identifier: 0000-0002-3212-9381
authors.initials: C
authors.lastname: Ruhrberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D002199:Capillary Permeability; D004789:Enzyme Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D039942:Neuropilin-1 / Q000502:physiology*; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D040121:Semaphorin-3A / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C115271:Gipc1 protein, mouse; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D039942:Neuropilin-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases