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: Because pPXN is recruited to focal adhesions to promote their turnover during cell migration (Zaidel-Bar et al., 2007; Pasapera et al., 2010) and NRP1-deficient ECs have reduced pPXN (Figs. 1 and 2), we examined NRP1-dependent pPXN localization in FN-stimulated HDMECs by immunostaining. In control cells, pPXN increased over time and was present in focal adhesions at the end of F-actin stress fibers, correlating with an elongated cell shape (Fig. 3 A). FN-stimulated HDMECs, therefore, displayed the hallmarks of polarized cells. Although VEGFR2 down-regulation did not impair these responses, HDMECs lacking NRP1 displayed their characteristic rounded morphology with abundant cortical actin; correlating with the lack of stress fibers, pPXN levels were significantly decreased, with remaining pPXN being localized mainly to the cell periphery (Fig. 3, A and B). Immunoblotting established that siRNA targeting had been effective and further confirmed reduced pPXN in NRP1-deficient cells (Fig. 3 B); in contrast, pPXN was slightly but significantly increased in VEGFR2-deficient cells (Fig. 3, B and C). These findings demonstrate that NRP1 promotes PXN phosphorylation in a VEGFR2-independent fashion.
Affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England UK email@example.com firstname.lastname@example.org.