1Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Sci Signal. 2014 Jan 7;7(307):ra1. doi: 10.1126/scisignal.2004235.
Although vascular complications are a hallmark of diabetes, the molecular mechanisms that underlie endothelial dysfunction are unclear. We showed that reactive oxygen species generated from hyperglycemia promoted ligand-independent phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2). This VEGFR2 signaling occurred within the Golgi compartment and resulted in progressively decreased availability of VEGFR2 at the cell surface. Consequently, the responses of endothelial cells to exogenous VEGF in a mouse model of diabetes were impaired because of a specific deficiency of VEGFR2 at the cell surface, despite a lack of change in transcript abundance. Hyperglycemia-induced phosphorylation of VEGFR2 did not require intrinsic receptor kinase activity and was instead mediated by Src family kinases. The reduced cell surface abundance of VEGFR2 in diabetic mice was reversed by treatment with the antioxidant N-acetyl-L-cysteine, suggesting a causative role for oxidative stress. These findings uncover a mode of ligand-independent VEGFR2 signaling that can progressively lead to continuously muted responses to exogenous VEGF and limit angiogenic events.
虽然血管并发症是糖尿病的一个标志，但内皮功能障碍的分子机制尚不清楚。我们表明，高血糖产生的活性氧促进了血管内皮生长因子受体 2（VEGFR2）的配体非依赖性磷酸化。这种 VEGFR2 信号发生在内质网隔室中，并导致细胞表面 VEGFR2 的可及性逐渐降低。因此，尽管转录物丰度没有变化，但由于细胞表面 VEGFR2 的特异性缺乏，糖尿病小鼠模型中外源性 VEGF 的内皮细胞反应受损。高血糖诱导的 VEGFR2 磷酸化不需要内在受体激酶活性，而是由 Src 家族激酶介导。抗氧化剂 N-乙酰-L-半胱氨酸的治疗逆转了糖尿病小鼠中 VEGFR2 的细胞表面丰度降低，表明氧化应激起因果作用。这些发现揭示了一种配体非依赖性 VEGFR2 信号传导模式，它可以逐渐导致对外源性 VEGF 的反应持续减弱，并限制血管生成事件。
