Androgen action augments ischemia-induced, bone marrow progenitor cell-mediated vasculogenesis

Abstract

Bone marrow-derived progenitor cell-mediated vasculogenesis is a key process for vascular repair and regeneration. However, the role of androgens in the mechanism of ischemia-induced vasculogenesis remains unclear. In this study, a gender-mismatch murine bone marrow transplant model was used to allow tissue tracking of transplanted cells. Bone marrow from 2-month-old male mice was transplanted into irradiated age-matched female recipients. Following the transplantation, ovariectomized female recipients were subjected to unilateral hindlimb ischemia and immediately implanted with either dihydrotestosterone (DHT) or placebo pellets. Laser Doppler perfusion imaging revealed that DHT significantly augmented blood flow recovery, with increased capillary density compared to placebo-treated female recipient controls. Flow cytometry analysis showed that DHT modulated vasculogenesis by increasing Sca1+/CXC4+ progenitor cell production in bone marrow and spleen and enhancing cell mobilization in circulating blood following hindlimb ischemia. Bone marrow cell homing was examined by detecting expression levels of male-specific SRY gene in the ischemic female tissues. DHT treatment promoted bone marrow cell homing to ischemic tissue shown by significantly higher SRY expression compared to placebo-treated females as well as reduced apoptotic features in DHT-treated females, including increased Bcl-2 expression, reduced Bax levels and decreased TUNEL staining. In conclusion, the gender-mismatched bone marrow transplant study shows that androgens directly enhance bone marrow cell-mediated vasculogenesis that contributes to ischemia-induced neovascularization.