Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization

Endothelial progenitor cells (EPCs) have been isolated from circulating mon onuclear cells in human peripheral blood and shown to be incorporated into foci of neovascularization, consistent with postnatal vasculogenesis'. We d etermined whether endogenous stimuli (tissue ischemia) and exogenous cytoki ne therapy (granulocyte macrophage-colony stimulating factor, GM-CSF) mobil ize EPCs and thereby contribute to neovascularization of ischemic tissues. The development of regional ischemia in both mice and rabbits increased the frequency of circulating EPCs. In mice, the effect of ischemia-induced EPC mobilization was demonstrated by enhanced ocular neovascularization after cornea micropocket surgery in mice with hindlimb ischemia compared with tha t in non-ischemic control mice. In rabbits with hindlimb ischemia, circulat ing EPCs were further augmented after pretreatment with CM-CSF, with a corr esponding improvement in hindlimb neovascularization. There was direct evid ence that EPCs that contributed to enhanced corneal neovascularization were specifically mobilized from the bone marrow in response to ischemia and GM -CSF in mice transplanted with bone marrow from transgenic donors expressin g P-galactosidase transcriptionally regulated by the endothelial cell-speci fic Tie-2 promoter. These findings indicate that circulating EPCs are mobil ized endogenously in response to tissue ischemia or exogenously by cytokine therapy and thereby augment neovascularization of ischemic tissues.