Di Qun, Cheng Zeen, Kim Weon, Liu Zexuan, Song Hui, Li Xiang, Nan Yongshan, Wang Chengya, Cheng Xianwu
The Department of Department of Geriatrics, The First Affiliated Hospital of Nanjing University, Nanjing, China.
Int J Cardiol. 2013 Oct 3;168(3):2167-76. doi: 10.1016/j.ijcard.2013.01.240. Epub 2013 Feb 27.
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.
Aging reduced the blood flow and vessel density in ischemic muscles in mice. Levels of phosphorylated Src (p-Src), p-β3, and p-VEGFR-2 in acute ischemia were reduced in the muscles of aged mice compared to young mice. The hypoxia-inducible factor (HIF)-1α 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 β3-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 β3-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 β3 tyrosine phosphorylation in hypoxia. Aging enhanced the hypoxia-induced EPC apoptosis and impaired several c-Src-related VEGF-induced receptor events, including β3 tyrosine activation, ligand binding, cell adhesion, and tubulogenesis in cultured EPCs of animals and those of humans.
These data suggest that the aging-related decline in angiogenic action in response to ischemia is mediated by the impairment of cross-activation between β3 and VEGFR-2 in EPCs, which is partially associated with decreased HIF-1α stability.
血管再生随衰老而下降的机制尚未完全明确。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。在此，我们研究了衰老是否会损害缺氧条件下内皮祖细胞（EPCs）中的这种相互作用。
衰老降低了小鼠缺血肌肉中的血流量和血管密度。与年轻小鼠相比，老年小鼠急性缺血时肌肉中磷酸化Src（p-Src）、p-β3和p-VEGFR-2的水平降低。缺氧诱导因子（HIF）-1α稳定剂去铁胺改善了与年龄相关的血管生成损伤，但这种作用被磷脂酰肌醇3激酶抑制剂LY290004减弱。去铁胺改善了老年小鼠肌肉中慢性缺血诱导的β3整合素和VEGFR-2磷酸化的降低；LY290004也减弱了这种作用。在EPCs中，我们确定了急性缺氧下玻连蛋白诱导的细胞黏附中VEGF介导的β3整合素和VEGFR-2交叉激活的分子要求。我们证明c-Src在缺氧条件下控制黏附及VEGF诱导的β3酪氨酸磷酸化。衰老增强了缺氧诱导的EPC凋亡，并损害了几种与c-Src相关的VEGF诱导的受体事件，包括动物和人类培养的EPCs中的β3酪氨酸激活、配体结合、细胞黏附和管状结构形成。
这些数据表明，衰老相关的缺血性血管生成作用下降是由EPCs中β3和VEGFR-2之间交叉激活受损介导的，这部分与HIF-1α稳定性降低有关。
