INTRODUCTION: Advanced age is a significant risk factor for vascular complications that involve a failure to create new blood vessels in response to ischemia. It has recently been shown that bone marrow derived vascular stem cells (EPC's) contribute significantly to neovascularization. The purpose of this study was to determine whether this process is impaired with increased age and if this occurs through impaired EPC function or through impaired trafficking of EPC's to sites of ischemia and injury.
METHODS: Peripheral blood samples were gathered from young (<25yo) and aged (>75yo) volunteers (n=20). EPC numbers were quantified by FACS analysis. Isolated EPC's were cultured for 7 days and migration towards SDF-1a and proliferation under hypoxic conditions were studied. Also, surgical samples were obtained from young and aged volunteers (n=20). Fibroblasts and vascular endothelial cells were cultured and exposed to normoxic and hypoxic conditions and levels of known EPC-recruiting HIF-responsive genes SDF-1 and VEGF were examined by real-time RT-PCR.
RESULTS: Circulating levels of EPC's were statistically identical between young and aged volunteers. Migration towards SDF-1 and proliferation under hypoxia were statistically similar between the two groups. While circulating EPC numbers and function were similar with advanced age, stromal cell function was dramatically reduced. Aged fibroblasts and vascular endothelial cells showed decreased stabilization of transcription factor HIF-1a compared to young cells. Aged stromal cells did not upregulate SDF-1 or VEGF in response to hypoxia compared to young cells.
CONCLUSION: Circulating numbers and function of adult vascular stem cells are preserved with advanced age. However, a defective stromal cell response to hypoxia with advanced age suggests that decreased trafficking of vascular stem cells to sites of ischemia may be responsible for the vascular complications associated with aging. This also suggests that while cellular function is preserved, pharmacological therapies augmenting adult stem cell homing to sites of ischemia could reverse age-related vascular disease.