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 examine if NRP1 and ABL1 also promote PXN phosphorylation in an ECM-dependent angiogenesis model in vivo, we studied the perinatal mouse retina; in this organ, endothelial sprouts headed by filopodia-studded tip cells migrate toward astrocyte-localized VEGF in the retinal periphery, with filopodia being guided by astrocyte-derived FN (Fig. 6 A; Ruhrberg et al., 2002; Gerhardt et al., 2003; Stenzel et al., 2011). Immunostaining confirmed FN deposition around IB4-stained vessels and ahead of the vascular front in a fine meshwork characteristic of astrocytes (Fig. 6 B). To investigate how NRP1 deficiency affected pPXN levels during retinal angiogenesis, we could not use Nrp1−/− mice, as they die before birth (Kawasaki et al., 1999). Instead, we compared Nrp1+/+ and Nrp1+/− littermates because the latter are viable but nevertheless have mild angiogenesis defects (Fantin et al., 2013). Immunoblotting confirmed significantly decreased NRP1 levels in P6 Nrp1+/− mice (Fig. 6 C). Single optical slices, acquired by confocal microscopy after immunolabeling, revealed pPXN staining in ECs at the IB4-positive vascular front, including tip cells and their filopodia, and also some pPXN ahead of the vascular front (Fig. 6 D). As observed for si-NRP1–targeted HDMECs, pPXN staining appeared reduced in Nrp1+/− littermates, both in vascular and avascular areas (Fig. 6 D). To confirm that this defect was cell autonomous in vascular endothelium, we also used Cre-LoxP recombination approach to delete NRP1 (Fig. 1). Thus, conditional Nrp1- mice lacking or expressing a tamoxifen-inducible, endothelial-specific Cre transgene were treated with tamoxifen from postnatal day 2 (P2) to P5 and stained for IB4 and pPXN. As seen in Nrp1+/− mice, tamoxifen-treatment reduced pPXN in Cre-expressing but not Cre-negative (control) littermates (Fig. 6 D).
Affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England UK email@example.com firstname.lastname@example.org.