Angiogenesis (VEGF)

Angiogenesis is the formation of new blood vessels from pre-existing capillaries, driven by vascular endothelial growth factor-A (VEGF-A), a glycoprotein that binds receptor tyrosine kinases VEGFR-1 and VEGFR-2 on endothelial cells, triggering proliferation, migration, and tube formation. VEGF expression is induced by tissue hypoxia via HIF-1α, by mechanical shear stress, and by the transcriptional coactivator PGC-1α, collectively matching capillary supply to metabolic demand. With advancing age, skeletal muscle undergoes capillary rarefaction: resting VEGF protein is approximately 35% lower and the exercise-induced rise in VEGF mRNA roughly 50% blunted in aged vs. young women (Croley et al. 2005), with parallel findings in aged men; capillary-to-fiber ratios decline by approximately 25% in older sedentary cohorts (Zmudzka et al. 2022). Regular aerobic training partially reverses this decline, raising capillary density up to ~28% and the capillary-to-fiber ratio up to ~43% even in older adults, through local hypoxia, nitric oxide signaling, and PGC-1α-mediated VEGF upregulation. Pharmacological VEGF delivery remains investigational with mixed results in peripheral artery disease trials; exercise is therefore the only established approach to restore age-related capillary loss.