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 firstname.lastname@example.org email@example.com.Show MeSH
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Mentions: Because FN stimulation activated NRP1-dependent actin remodeling and cell migration independently of VEGF165 and VEGFR2, we sought to identify candidate effectors with a phosphokinase antibody array (e.g., Zhuang et al., 2012). For this experiment, HDMECs were transfected with si-NRP1 or control siRNA (Fig. 2 A), and then serum-starved and stimulated with VEGF165 (Fig. 2 B) or plated on FN (Fig. 2 C). We observed reduced VEGF165-induced activation of the MAPK p38 in ECs lacking NRP1, as expected (Kawamura et al., 2008), and additionally impaired FN-induced P38 activation in ECs lacking NRP1 (Fig. 2, B and C). The screen also showed that NRP1 down-regulation in VEGF165-stimulated HDMECs reduced AKT activation (Fig. 2 B), as previously reported for HUVECs (Pan et al., 2007a,b; Koch et al., 2011). Unexpectedly, however, NRP1 down-regulation did not impair AKT phosphorylation in FN-stimulated ECs (Fig. 2 C).
Affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England UK firstname.lastname@example.org email@example.com.