Age-dependent impairment of angiogenesis

Background-The effect of aging on angiogenesis in ischemic vascular disease has not been studied. Accordingly, we investigated the hypothesis that ang iogenesis is impaired as a function of age. Methods and Results-Forty days after the resection of 1 femoral artery, col lateral vessel development was significantly impaired in old (aged 4 to 5 y ears; n=7) versus young (aged 6 to 8 months; n=6) New Zealand White (NZW) r abbits on the basis of reduced hindlimb perfusion (ischemic: normal blood p ressure ratio=0.58+/-0.05 versus 0.77+/-0.06; P<0.005), reduced number of a ngiographically visible vessels (angiographic score=0.48+/-0.05 versus 0.70 +/-0.05; P<0.01), and lower capillary density in the ischemic limb (1303+/- 5.8/mm(2) versus 171.4+/-9.5/mm(2); P<0.001). Angiogenesis was also impaire d in old (aged 2 years) versus young (aged 12 weeks) mice as shown by reduc ed hindlimb perfusion (measured by laser Doppler imaging) and lower capilla ry density (353.0+/-14.3/mm(2) versus 713.3+/-63.4/mm(2); P<0.01). Impaired angiogenesis in old animals was the result of impaired endothelial functio n (lower basal NO release and decreased vasodilation in response to acetylc holine) and a lower expression of vascular endothelial growth factor (VEGF) in ischemic tissues (by Northern blot, Western blot, and immunohistochemis try). When recombinant VEGF protein was administered to young and old rabbi ts, both groups exhibited a significant and similar increase in blood press ure ratio, angiographic score, and capillary density. Conclusions-Angiogenesis responsible for collateral development in limb isc hemia is impaired with aging; responsible mechanisms include age-related en dothelial dysfunction and reduced VEGF expression. Advanced age, however, d oes not preclude augmentation of collateral vessel development in response to exogenous angiogenic cytokines.