The Role of Androgens in Modulation of Bone Marrow-Derived Progenitor Cell-Mediated Vasculogenesis

Background: Men with lower endogenous androgen levels are at higher risk of cardiovascular disease (CVD). It has been shown that androgen levels correlate with baseline circulating progenitor cells, a predictor of future CVD occurrence. The proliferation, mobilisation and homing of bone marrow (BM) derived-progenitor cell are key players in vascular repair and regeneration known as vasculogenesis. The role of androgens in modulating vasculogenesis remain unclear. Method and Results: In a gender-mismatched murine BM transplant model, BM from 2-month-old male C57BL/6 J mice was transplanted into irradiated age-matched female recipients. After 6-week recovery, ovariectomised females were subjected to unilateral hindlimb ischaemia and were implanted with either dihydrotestosterone (DHT) or placebo pellets. Laser Doppler Perfusion Imaging revealed that DHT significantly augmented blood flow recovery in females, with increased capillary density compared to placebo-treated females. Sca1+/CXCR4+ progenitor cell levels in BM, spleen and circulating blood of females were analysed by flow cytometry post-ischaemia. DHT significantly increased Sca1+/CXCR4+ progenitor cell levels in BM, spleen and circulating blood in females indicating that androgens augment progenitor cell proliferation and mobilisation. This enhancement of vasculogenesis was independent of tissue angiogenic response in females, with no difference in the levels of CXCR4 ligand, stromal cell derived factor-1, in both treatment groups. Furthermore, qPCR analysis showed that the levels of male-specific SRY gene expression was markedly increased in the ischaemic tissues of DHT-treated females, indicating that androgens promote BM cell homing. Conclusion: Androgens enhance vasculogenesis by promoting the proliferation, mobilisation and homing of BM-derived progenitor cells following ischaemia.