UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England UK
UCL Institute of Ophthalmology, University College London, London EC1V 9EL, England UK.
J Exp Med. 2014 Jun 2;211(6):1167-83. doi: 10.1084/jem.20132330. Epub 2014 May 26.
To enable new blood vessel growth, endothelial cells (ECs) express neuropilin 1 (NRP1), and NRP1 associates with the receptor tyrosine kinase VEGFR2 after binding the vascular endothelial growth factor A (VEGF) to enhance arteriogenesis. We report that NRP1 contributes to angiogenesis through a novel mechanism. In human and mouse ECs, the integrin ligand fibronectin (FN) stimulated actin remodeling and phosphorylation of the focal adhesion component paxillin (PXN) in a VEGF/VEGFR2-independent but NRP1-dependent manner. NRP1 formed a complex with ABL1 that was responsible for FN-dependent PXN activation and actin remodeling. This complex promoted EC motility in vitro and during angiogenesis on FN substrates in vivo. 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.
为了促进新血管的生长，内皮细胞（ECs）会表达神经纤毛蛋白 1（NRP1），并且在与血管内皮生长因子 A（VEGF）结合后，NRP1 与受体酪氨酸激酶 VEGFR2 结合，以增强动脉生成。我们报告 NRP1 通过一种新的机制促进血管生成。在人源和鼠源 ECs 中，整合素配体纤维连接蛋白（FN）在 VEGF/VEGFR2 非依赖性但 NRP1 依赖性的方式下刺激肌动蛋白重塑和粘着斑组件整联蛋白连接激酶（PXN）的磷酸化。NRP1 与 ABL1 形成复合物，该复合物负责 FN 依赖性 PXN 激活和肌动蛋白重塑。该复合物促进了细胞体外迁移，以及在体内 FN 底物上的血管生成过程中的迁移。因此，视网膜中的生理性和病理性血管生成均被 ABL1 的小分子抑制剂伊马替尼抑制，伊马替尼广泛用于预防表达 BCR-ABL 融合蛋白的肿瘤细胞的增殖。这一发现表明，NRP1 通过 ABL1 以 VEGF 和 VEGFR2 非依赖性的方式调节血管生成，这提示 ABL1 抑制为抗血管生成治疗提供了一个新的机会，可与眼部疾病或实体瘤生长中 VEGFR2 或 VEGF 的阻断相补充。
