Imatinib inhibits VEGF-independent angiogenesis by targeting neuropilin 1-dependent ABL1 activation in endothelial cells.
Bottom Line: NRP1 formed a complex with ABL1 that was responsible for FN-dependent PXN activation and actin remodeling.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.
Affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England UK email@example.com firstname.lastname@example.org.Show MeSH
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Mentions: To assess the relevance of the FN-induced NRP1–ABL1 pathway for pathological vessel growth, we used a mouse model of oxygen-induced retinopathy (OIR; Connor et al., 2009). In this model, the sequential exposure of mouse pups to hyperoxia followed by normoxia leads to the formation of retinal neovascular lesions that resemble those observed in PDR patients and in babies with ROP, which arises after moving them out of incubators with high oxygen tension (Connor et al., 2009). Specifically, the exposure of neonatal mice to hyperoxia from P7 to P12 induces vasoobliteration of central retinal capillaries, which causes central retinal hypoxia on return to room air. The ensuing up-regulation of VEGF and other proangiogenic factors then activates angiogenesis, but this process fails to effectively revascularize the retina and instead leads to abundant tuft-like vascular malformations that protrude into the vitreous (Smith et al., 1994). Immunostaining of flat-mounted retinas on P17, 5 days after return to room air, showed that these neovascular tufts were FN positive (Fig. 8 A), suggesting that OIR is a suitable model to examine the role of NRP1 and ABL1 in ECM-mediated angiogenesis pathways. In agreement, Imatinib treatment of mouse pups from their return to normoxia until P17 significantly reduced revascularization of avascular areas (AV; Fig. 8, B and C) and effectively inhibited the formation of neovascular tufts (Fig. 8, B–D).
Affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England UK email@example.com firstname.lastname@example.org.