Abstract 15008: Androgens Ameliorate Age-Related Impairment in Ischemia-Mediated Neovascularization by Enhancement of Androgen-Receptor Dependent, Endothelial Progenitor Cell (EPC)-Mediated Vasculogenesis
Introduction: Increasing evidence indicates that androgen regulates angiogenesis. In aging men, a progressively decline in circulating androgens is coincident with cardiovascular disease. This study elucidated the role of androgens in ischemia-mediated neovascularization in young and old animals.
Methods: In a murine hindlimb ischemia (HLI) model, dihydrotestosterone (DHT) or placebo (P) was implanted in young (2-month), androgen receptor knockout (ARKO) (2-month) and old (24-month) mice post-HLI. The blood flow recovery was monitored by Laser Doppler. Bone marrow EPCs were ex vivo cultured for DHT treatment.
Results: Aging was associated with marked impairment in ischemic recovery after HLI. DHT augmented blood flow recovery in young mice and significantly attenuated age-related impairment of ischemic recovery in old mice after HLI (young; DHT vs. P, 0.92±0.18 vs. 0.72±0.21, p<0.05. Old; DHT vs. P, 0.34±0.05 vs. 0.16±0.05, p<0.01). In old mice, DHT augmented EPC proliferation (DHT vs. P, 5.64±1.12 vs. 3.02±0.31, p<0.05) and restored age-related impairment in EPC mobilization (DHT vs. P, 23.65±2.51 vs. 15.64±1.86, p<0.01) to levels not different to young mice. DHT treatment increased ex vivo cultured EPC migration toward stromal derived factor-1 compared to untreated EPCs (young; 1.59±0.18, p<0.05. Old; 1.89±0.22, p<0.01), which was inhibited by androgen receptor (AR) antagonist, hydroxyflutamide. DHT-augmented EPC proliferation and mobilization were absent in ARKO mice, which lacked the DHT-enhanced improvement in blood flow recovery post HLI. In young mice, DHT induced 2-fold increase in AR and key angiogenesis genes in ischemic tissues, including hypoxia inducible factor-1α (HIF-1α) (DHT vs. P, 3.84±0.77 vs. 1.98±0.18, p<0.05) and stromal derived factor-1 (DHT vs. P, 2.88±0.74 vs. 1.64±0.22, p<0.05). Unlike young mice, AR and HIF-1α in the ischemic tissues of old mice were unresponsive to DHT treatment.
Conclusions: Androgen replacement attenuates age-related impairment of ischemia-mediated neovascularization via enhancement of AR-dependent, EPC-mediated vasculogenesis. By comparison to young mice, aging is associated with loss of androgen augmentation of key angiogenesis mechanisms in ischemic tissues.
Author Disclosures: Y. Lam: None. L. Lecce: None. S. Yuen: None. D.J. Handelsman: None. R. Karas: None. M.K. Ng: None.
- © 2014 by American Heart Association, Inc.