Abstract
Introduction: Increasing evidence indicates that androgens regulate ischemia-induced neovascularization. However, the role of androgen receptor (AR), a ligand-dependent nuclear transcription factor, remains poorly understood with genomic and non-genomic mechanisms proposed. Hypothesis: Using AR knockout mice (ARKO), which contain a transcriptionally inactive AR due to an in-frame deletion of the second zinc finger of the DNA-binding domain of AR, we hypothesized that AR genomic function plays a role in modulating androgen-mediated augmentation of ischemia-induced neovascularization. Methods and Results: Wild type (ARWT) and ARKO were implanted with dihydrotestosterone (DHT) or placebo (P) pellets following induction of hindlimb ischemia (HLI). Laser Doppler Perfusion Imaging revealed that DHT enhanced blood flow recovery in ARWT post-HLI. By contrast, DHT-mediated enhancement of blood flow recovery was abrogated in ARKO. Ischemia-induced vasculogenesis was examined by flow cytometry to assess the levels of Sca1+/CXCR4+ progenitor cells. DHT augmented the levels of Sca1+/CXCR4+ progenitor cells in bone marrow (DHT: 10.87 ± 0.817 vs. P: 5.057 ±0.503, p<0.001) and circulating blood (DHT: 8.827 ± 1.122 vs. P: 5.150 ± 0.924) in ARWT at day 3 post-HLI. The augmentation of bone marrow and circulating Sca1+/CXCR4+ progenitor cell levels by DHT was absent in ARKO post-HLI. Transplantation of ARWT or ARKO bone marrow into irradiated recipients further revealed that ischemia-induced elevation of circulating progenitor cells was abolished in recipients with ARKO bone marrow. DHT augmented ischemia-induced HIF-1α expression (DHT: 2.39- vs. P: 1.4-fold increase at day 3 post HLI, p<0.05) and promoted the production of stromal derived factor-1 (SDF-1) in ARWT. However, DHT augmentation of HIF-1α and SDF-1 were attenuated in ARKO post-HLI. In vitro, DHT-induced HIF-1α transcriptional activity and DHT-augmented tubule formation of endothelial cells via paracrine effect were attenuated in cells isolated from ARKO. Conclusions: Augmentation of ischemia-induced bone marrow-derived progenitor cell mobilization and HIF-1α-associated angiogenesis by androgens is dependent on the genomic action of AR.
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