Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization

Circulating endothelial progenitor cells (EPCs) have been isolated in perip heral blood of adult species. To determine the origin and role of EPCs cont ributing to postnatal vasculogenesis, transgenic mice constitutively expres sing beta-galactosidase under the transcriptional regulation of an endothel ial cell-specific promoter (Flk-1/LZ or Tie-2/LZ) were used as transplant d onors. Localization of EPCs, indicated by flk-1 or tie-2/lacZ fusion transc ripts, were identified in corpus luteal and endometrial neovasculature afte r inductive ovulation. Mouse syngeneic colon cancer cells (MCA38) were impl anted subcutaneously into Flk-1/LZ/BMT (bone marrow transplantation) and Ti e-2/LZ/BMT mice; tumor samples harvested at 1 week disclosed abundant flk-1 /lacZ and tie-2/lacZ fusion transcripts, and sections stained with X-gal de monstrated that the neovasculature of the developing tumor frequently compr ised Flk-1- or Tie-2-expressing EPCs. Cutaneous wounds examined at 4 days a nd 7 days after skin removal by punch biopsy disclosed EPCs incorporated in to foci of neovascularization at high frequency. One week after the onset o f hindlimb ischemia, lacZ-positive EPCs were identified incorporated into c apillaries among skeletal myocytes. After permanent ligation of the left an terior descending coronary artery, histological samples from sites of myoca rdial infarction demonstrated incorporation of EPCs into foci of neovascula rization at the border of the infarct. These findings indicate that postnat al neovascularization does not rely exclusively on sprouting from preexisti ng blood vessels (angiogenesis); instead, EPCs circulate from bone marrow t o incorporate into and thus contribute to postnatal physiological and patho logical neovascularization, which is consistent with postnatal vasculogenes is.