title: Defective CXCR4 expression in aged bone marrow cells impairs vascular regeneration.
abstract: The chemokine stromal cell-derived factor-1 (SDF-1) plays a critical role in mobilizing precursor cells in the bone marrow and is essential for efficient vascular regeneration and repair. We recently reported that calcium augments the expression of chemokine receptor CXCR4 and enhances the angiogenic potential of bone marrow derived cells (BMCs). Neovascularization is impaired by aging therefore we suggested that aging may cause defects of CXCR4 expression and cellular responses to calcium. Indeed we found that both the basal and calcium-induced surface expression of CXCR4 on BMCs was significantly reduced in 25-month-old mice compared with 2-month-old mice. Reduced Ca-induced CXCR4 expression in BMC from aged mice was associated with defective calcium influx. Diminished CXCR4 surface expression in BMC from aged mice correlated with diminished neovascularization in an ischemic hindlimb model with less accumulation of CD34(+)  progenitor cells in the ischemic muscle with or without local overexpression of SDF-1. Intravenous injection of BMCs from old mice homed less efficiently to ischemic muscle and stimulated significantly less neovascularization compared with the BMCs from young mice. Transplantation of old BMCs into young mice did not reconstitute CXCR4 functions suggesting that the defects were not reversible by changing the environment. We conclude that defects of basal and calcium-regulated functions of the CXCR4/SDF-1 axis in BMCs contribute significantly to the age-related loss of vasculogenic responses.
authors.affiliation: Vascular Biology Institute, University of Miami, Miller School of Medicine, Miami, FL, USA.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Shao
authors.forename: Qiyuan
authors.initials: Q
authors.lastname: Xu
authors.forename: Qiuling
authors.initials: Q
authors.lastname: Wu
authors.forename: Qi
authors.initials: Q
authors.lastname: Ma
authors.forename: Luis
authors.initials: L
authors.lastname: Salgueiro
authors.forename: Jian'An
authors.initials: J
authors.lastname: Wang
authors.forename: Darwin
authors.initials: D
authors.lastname: Eton
authors.forename: Keith A
authors.initials: KA
authors.lastname: Webster
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D016922:Cellular Senescence; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006614:Hindlimb / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism*; D012038:Regeneration; D013234:Stem Cells / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C527276:CXCR4 protein, human; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A; D002118:Calcium