No abstract

Background-Advanced age is known to impair neovascularization. Because endothelial progenitor cells (EPCs) participate in this process, we examined the effects of aging on EPC recruitment and vascular incorporation. Methods and Results-Murine neovascularization was examined by use of an ischemic flap model, which demonstrated aged mice (19 to 24 months) had decreased EPC mobilization (percent mobilized 1.4Ϯ0.2% versus 0.4Ϯ0.1%, PϽ0.005) that resulted in impaired gross tissue survival compared with young mice (2 to 6 months). This decrease correlated with diminished tissue perfusion (PϽ0.005) and decreased CD31 ϩ vascular density (PϽ0.005). Gendermismatched bone marrow transplantation demonstrated significantly fewer chimeric vessels in aged mice (PϽ0.05), which confirmed a deficit in bone marrow-mediated vasculogenesis. Age had no effect on total EPC number in mice or humans. Reciprocal bone marrow transplantations confirmed that impaired neovascularization resulted from defects in the response of aged tissue to hypoxia and not from intrinsic defects in EPC function. We demonstrate that aging decreased hypoxia-inducible factor 1␣ stabilization in ischemic tissues because of increased prolyl hydroxylasemediated hydroxylation (PϽ0.05) and proteasomal degradation. This resulted in a diminished hypoxia response, including decreased stromal cell-derived factor 1 (PϽ0.005) and vascular endothelial growth factor (PϽ0.0004). This effect can be reversed with the iron chelator deferoxamine, which results in hypoxia-inducible factor 1␣ stabilization and increased tissue survival. Conclusions-Aging impairs EPC trafficking to sites of ischemia through a failure of aged tissues to normally activate the hypoxia-inducible factor 1␣-mediated hypoxia response.

The virulence of cell surface-associated, glucan synthesis-defective mutants of Streptococcus mutans strain 6715-13 was studied. Representatives from three groups of such mutants were tested for their pathogenicity in conventionalized, specific pathogen-free rats and gnotobiotic rats. The mutants differ from the wild-type strain in that each failed to form plaque on the smooth surfaces of the teeth and to cause smooth surface caries. Although the ability to form cell surface-associated glucans was not a strict requirement for the expression of virulence in the sulci of the teeth, it augmented virulence at such sites. However, the ability to form cell surface-associated glucans and to adhere to the teeth was clearly not the sole determinant of virulence.