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 NRP1 is known to interact with FN-binding integrins (Fukasawa et al., 2007; Robinson et al., 2009; Valdembri et al., 2009), we first examined the requirement of NRP1 for EC adhesion, spreading, and actin remodeling. For these experiments, we used human dermal microvascular ECs (HDMECs) because dermal vasculature naturally undergoes extensive angiogenesis during wound healing. We additionally used human umbilical vein ECs (HUVECs), as they have been widely used to study VEGF-induced signaling mechanisms (e.g., Soker et al., 2002; Pan et al., 2007a; Chen et al., 2010). We transfected primary cells with a previously validated siRNA that targets NRP1 or a control nonsense siRNA. Having confirmed the efficacy of this approach (Fig. 1 A), we tested HDMEC and HUVEC adhesion to tissue culture dishes coated with 10 µg/ml FN, a concentration which effectively promotes cell adhesion and migration (Clark et al., 1986; Sottile et al., 1998; Tvorogov et al., 2005). In contrast to earlier studies, which reported that NRP1 loss inhibits HUVEC adhesion at FN concentrations <5 µg/ml (Murga et al., 2005; Valdembri et al., 2009), we found that adhesion was not compromised by NRP1 deficiency in either HDMECs or HUVECs at 10 µg/ml FN (Fig. 1, B and C). We had therefore identified conditions suitable to study FN-induced cell spreading, actin remodeling, and cell migration of ECs in the absence of prior defects in cell attachment.
Affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England UK email@example.com firstname.lastname@example.org.