title: Impaired cross-activation of β3 integrin and VEGFR-2 on endothelial progenitor cells with aging decreases angiogenesis in response to hypoxia.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  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 β3 and VEGFR-2 in EPCs, which is partially associated with decreased HIF-1α stability.
authors: The Department of Department of Geriatrics, The First Affiliated Hospital of Nanjing University, Nanjing, China.
authors: Qun
authors: Q
authors: Di
authors: Zeen
authors: Z
authors: Cheng
authors: Weon
authors: W
authors: Kim
authors: Zexuan
authors: Z
authors: Liu
authors: Hui
authors: H
authors: Song
authors: Xiang
authors: X
authors: Li
authors: Yongshan
authors: Y
authors: Nan
authors: Chengya
authors: C
authors: Wang
authors: Xianwu
authors: X
authors: Cheng
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D066026:Endothelial Progenitor Cells / Q000378:metabolism* / Q000473:pathology; D005500:Follow-Up Studies; D006614:Hindlimb / Q000098:blood supply; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D039661:Integrin beta3 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000502:physiology* / Q000528:radiation effects*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D039661:Integrin beta3; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Aging; Angiogenesis; Hypoxia-induced factor-1α; Vascular endothelial growth factor receptor-2; β(3)-Integrin