VEGF165-induced vascular permeability requires NRP1 for ABL-mediated SRC family kinase activation.
VEGF165-induced vascular permeability requires NRP1 for ABL-mediated SRC family kinase activation.
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DOI：
10.1084/jem.20160311
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发表时间：
2017-04-03
期刊：
影响因子：
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通讯作者：
Ruhrberg C
中科院分区：
文献类型：
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作者：
Fantin A;Lampropoulou A;Senatore V;Brash JT;Prahst C;Lange CA;Liyanage SE;Raimondi C;Bainbridge JW;Augustin HG;Ruhrberg C
范廷等人。显示 VEGF 亚型 VEGF165 通过 VEGFR2 和 NRP1 的复合物发出信号，其中 NRP1 胞质结构域促进 ABL 介导的 SRC 家族激酶激活，从而引起通透性过高反应，这是病理性水肿的已知原因。血管内皮生长因子 (VEGF) 异构体 VEGF165 刺激血管生长和通透性过高。虽然血管生长对于维持器官健康至关重要，但慢性渗透性过高会导致破坏性组织水肿。通过结合体内和组织培养模型，我们在此表明 VEGF165 诱导的血管渗漏需要 VEGFR2 和 NRP1，包括 NRP1 的 VEGF164 结合位点和 NRP1 胞质结构域 (NCD)，但不需要已知的 NCD 相互作用蛋白 GIPC1。在 VEGF165 结合受体复合物中，NCD 促进 ABL 激酶激活，而 ABL 激酶又是激活 VEGFR2 招募的 SRC 家族激酶 (SFK) 所必需的。这些结果阐明了受体复合物和下游激酶的信号传导层次，这些激酶可转导对 VEGF165 的通透性反应。在具有类似于年龄相关性黄斑变性的脉络膜新生血管形成的小鼠模型中，NCD 损失减轻了血管渗漏而不影响新生血管形成。这些发现提出了一种可能性，即靶向 NRP1 或其 NCD 相互作用因子可能是新生血管疾病的一种有用的治疗策略，可在不影响血管生长的情况下减少 VEGF165 诱导的水肿。
Fantin et al. show that the VEGF isoform VEGF165 signals through a complex of VEGFR2 and NRP1, in which the NRP1 cytoplasmic domain promotes the ABL-mediated activation of SRC family kinases to evoke a hyperpermeability response, a known cause of pathological edema. The vascular endothelial growth factor (VEGF) isoform VEGF165 stimulates vascular growth and hyperpermeability. Whereas blood vessel growth is essential to sustain organ health, chronic hyperpermeability causes damaging tissue edema. By combining in vivo and tissue culture models, we show here that VEGF165-induced vascular leakage requires both VEGFR2 and NRP1, including the VEGF164-binding site of NRP1 and the NRP1 cytoplasmic domain (NCD), but not the known NCD interactor GIPC1. In the VEGF165-bound receptor complex, the NCD promotes ABL kinase activation, which in turn is required to activate VEGFR2-recruited SRC family kinases (SFKs). These results elucidate the receptor complex and signaling hierarchy of downstream kinases that transduce the permeability response to VEGF165. In a mouse model with choroidal neovascularisation akin to age-related macular degeneration, NCD loss attenuated vessel leakage without affecting neovascularisation. These findings raise the possibility that targeting NRP1 or its NCD interactors may be a useful therapeutic strategy in neovascular disease to reduce VEGF165-induced edema without compromising vessel growth.