title: Imatinib inhibits VEGF-independent angiogenesis by targeting neuropilin 1-dependent ABL1 activation in endothelial cells.
abstract: To enable new blood vessel growth, endothelial cells (ECs) express neuropilin 1 (NRP1), and NRP1 associates with the receptor tyrosine kinase VEGFR2 after binding the vascular endothelial growth factor A (VEGF) to enhance arteriogenesis. We report that NRP1 contributes to angiogenesis through a novel mechanism. In human and mouse ECs, the integrin ligand fibronectin (FN) stimulated actin remodeling and phosphorylation of the focal adhesion component paxillin (PXN) in a VEGF/VEGFR2-independent but NRP1-dependent manner. NRP1 formed a complex with ABL1 that was responsible for FN-dependent PXN activation and actin remodeling. This complex promoted EC motility in vitro and during angiogenesis on FN substrates in vivo. Accordingly, both physiological and pathological angiogenesis in the retina were inhibited by treatment with Imatinib, a small molecule inhibitor of ABL1 which is widely used to prevent the proliferation of tumor cells that express BCR-ABL fusion proteins. The finding that NRP1 regulates angiogenesis in a VEGF- and VEGFR2-independent fashion via ABL1 suggests that ABL1 inhibition provides a novel opportunity for anti-angiogenic therapy to complement VEGF or VEGFR2 blockade in eye disease or solid tumor growth.
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England UK c.raimondi@ucl.ac.uk c.ruhrberg@ucl.ac.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: 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: Laura
authors.initials: L
authors.lastname: Denti
authors.affiliation: Centre for Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary London University, London E1 2AT, England UK.
authors.forename: Anissa
authors.initials: A
authors.lastname: Chikh
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England UK c.raimondi@ucl.ac.uk c.ruhrberg@ucl.ac.uk.
authors.forename: Christiana
authors.initials: C
authors.lastname: Ruhrberg
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism*; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D015861:Retinal Neovascularization / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D001549:Benzamides; D005353:Fibronectins; D051419:Paxillin; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D000068877:Imatinib Mesylate; D040301:Vascular Endothelial Growth Factor Receptor-2; D016315:Proto-Oncogene Proteins c-abl