Abstract 630: Effects of Chronic Exercise on Restoring Age-impaired VEGF Upregulation and Angiogenetic Responses to Hindlimb Ischemia
Alterations in hypoxia-inducible factor 1α (HIF-1α) activity and vascular endothelial growth factor (VEGF) expression in ischemic tissues are involved in age-dependent impairment of angiogenesis. We explored whether chronic exercise restores these molecular mechanisms and improves neoangiogenesis in aged rats with hindlimb ischemia. Our protocol included 15 young and 15 old WKY rats, trained with a 12 week treadmill exercise program performed before unilateral hindlimb ischemia. 15 young and 15 old sedentary rats were also included. Ischemia-induced increase of HIF-1α (Western blot analysis) was lower in untrained old (P <.0001), while it was comparable in trained young and old animals. Electromobility shift assay showed a specific tissue HIF-1α DNA binding activity in trained old but not in untrained old animals. Ischemia-induced VEGF upregulation was not evident in untrained old rats, although it was restored by exercise (P<.0001 ischemic vs non ischemic). In both age groups, exercise increased capillary density in ischemic muscles (P< .003 old trained vs untrained) although the ultimate levels was lower in olders (P< .0001). Histologic data were paralleled by angiographic (Digital angiography TIMI score) and perfusional (dyed beads dilution assay) results that indicated a more negative effect of ischemia on limb perfusion of untrained old rats (P< .0001 vs untrained young) and a significant improvement of blood flow induced by exercise in both age groups (P< .0001 untrained old; P < .0001 vs untrained young). A significant improvement in maximal exercise capacity was found in trained aged animals (P < .0001 vs untrained). The reduction of serum VEGF levels (ELISA) in trained vs untrained old rats (P< .003) reflected the comprehensive improvement in local ischemia evoked by exercise. Accordingly, data obtained from elderly humans with peripheral obstructive artery disease (PAOD) indicate that a lifestyle characterized by higher levels of physical activity is associated with reduced systemic VEGF levels. In conclusion, our data demonstrate that chronic exercise counteracts age-related molecular alterations resulting in impaired angiogenesis. This could have important clinical implications due to the high prevalence of PAOD in the elderly.