Tissue responses to ischemia tein. In these anemic sheep fetuses, increased cardiac output provides systemic compensation for decreased oxygen-carrying capacity. The increased cardiac work and mass increase myocardial oxygen consumption, thus providing a hypoxic stimulus for increased HIF-1α expression and HIF-1–mediated VEGFgene transcription. Temporo-spatial correlations between HIF-1α protein and VEGF mRNA expression have also been demonstrated in the context of developmental and ischemic vascularization of the mouse retina (16). Why does this response pathway fail to provide sufficient neovascularization in patients with coronary artery disease to prevent ischemia? One major difference is that the fetal sheep heart is a growing organ that is actively engaged in angiogenesis. Although this suggests differences in angiogenic responses as a function of developmental stage, aging in general may be an important factor. The absence of collateralization in some patients with symptomatic coronary artery disease may reflect impaired ability to produce VEGF. Ischemia-induced VEGF expression is likely to be influenced by a combination of genetic and environmental factors. Recent studies described below suggest that both aging and individual variability in responses to ischemia may influence the outcome of atherosclerotic vascular disease.

Collateral vessel development following femoral artery ligation is significantly reduced in older mice and rabbits (17). The impairment in vascularization is multifactorial, as older animals exhibit impaired VEGF production, vascular endothelial cell dysfunction, and reduced lymphocytic infiltration of ischemic tissues. Aortic smooth muscle cells from old rabbits manifest impaired hypoxia-induced VEGF expression due to a reduction in HIF-1 DNA-binding activity (18). HIF-1 DNA-binding activity is also reduced in brain, kidney, liver, and lung tissue from old versus young mice subjected to hypoxia (19).