Impaired cross-activation of β3 integrin and VEGFR-2 on endothelial progenitor cells with aging decreases angiogenesis in response to hypoxia
Impaired cross-activation of β3 integrin and VEGFR-2 on endothelial progenitor cells with aging decreases angiogenesis in response to hypoxia
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DOI：
10.1016/j.ijcard.2013.01.240
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发表时间：
2013-10-03
影响因子：
3.5
通讯作者：
Cheng, Xianwu
中科院分区：
文献类型：
--
作者：
Di, Qun;Cheng, Zeen;Cheng, Xianwu
背景：血管再生随年龄增长而衰退的机制尚未完全清楚。整合素与血管内皮生长因子受体-2（VEGFR-2）之间的相互作用在血管生成中起重要作用。在这里，我们调查是否老化损害这种相互作用的内皮祖细胞（EPCs）缺氧。方法和结果：老化减少了小鼠缺血性肌肉的血流量和血管密度。与年轻小鼠相比，老年小鼠肌肉中磷酸化Src（p-Src）、p-beta（3）和p-VEGFR-2的水平在急性缺血中降低。缺氧诱导因子（HIF）-1 α稳定剂去铁胺改善了年龄相关的血管生成障碍，但这种作用被磷脂酰肌醇3-激酶抑制剂LY 290004减弱。去铁胺改善了老年小鼠肌肉中慢性缺血诱导的β（3）-整合素和VEGFR-2磷酸化的减少; LY 290004也减弱了这种作用。在内皮祖细胞中，我们确定了急性缺氧条件下，在玻连蛋白诱导的细胞粘附中VEGF介导的β（3）-整合素和VEGFR-2交叉激活的分子要求。我们证明，c-Src控制的粘附和VEGF诱导的β（3）酪氨酸磷酸化在缺氧。衰老增强了缺氧诱导的EPC凋亡，并损害了几个c-Src相关的VEGF诱导的受体事件，包括β 3酪氨酸激活，配体结合，细胞粘附，以及动物和人类培养的EPC中的小管形成。这些数据表明，衰老相关的缺血性血管生成作用的下降是由β 3和VEGFR-1之间的交叉激活损伤介导的。2，这与HIF-1 α稳定性降低部分相关。(C)2013爱思唯尔爱尔兰有限公司版权所有。
Background: The mechanism by which vascular regeneration declines with aging is not fully understood. An interaction between integrin and vascular endothelial growth factor receptor-2 (VEGFR-2) plays a substantial role in angiogenesis. Here, we investigated whether aging impairs this interaction in endothelial progenitor cells (EPCs) under hypoxia.Methods and results: Aging reduced the blood flow and vessel density in ischemic muscles in mice. Levels of phosphorylated Src (p-Src), p-beta(3), and p-VEGFR-2 in acute ischemia were reduced in the muscles of aged mice compared to young mice. The hypoxia-inducible factor (HIF)-1 alpha stabilizer deferoxamine improved the age-related impairment of angiogenesis, but this effect was diminished by LY290004, an inhibitor of phosphatidylinositol 3-kinase. Deferoxamine improved the reduction in chronic ischemia-induced beta(3)-integrin and VEGFR-2 phosphorylation in the muscles of aged mice; this effect was also diminished by LY290004. In EPCs, we identified the molecular requirements for VEGF-mediated beta(3)-integrin and VEGFR-2 cross-activation in vitronectin-induced cell adhesion under acute hypoxia. We demonstrated that c-Src controlled the adhesion- and VEGF-induced beta(3) tyrosine phosphorylation in hypoxia. Aging enhanced the hypoxia-induced EPC apoptosis and impaired several c-Src-related VEGF-induced receptor events, including beta(3) tyrosine activation, ligand binding, cell adhesion, and tubulogenesis in cultured EPCs of animals and those of humans.Conclusions: These data suggest that the aging-related decline in angiogenic action in response to ischemia is mediated by the impairment of cross-activation between beta(3) and VEGFR-2 in EPCs, which is partially associated with decreased HIF-1 alpha stability. (C) 2013 Elsevier Ireland Ltd. All rights reserved.