Androgens Stimulate EPC-Mediated Neovascularization and Are Associated with Increased Coronary Collateralization

Endothelial progenitor cells (EPCs) play a key role in neovascularization and have been linked to improved cardiovascular outcomes. Although there is a well-established inverse relationship between androgen levels and cardiovascular mortality in men, the role of androgens in EPC function is not fully understood. In this study, we investigated the effects of androgens on two subpopulations of EPCs, early EPCs (EEPCs) and late outgrowth EPCs (OECs), and their relationship with coronary collateralization. EEPCs and OECs were isolated from the peripheral blood of young healthy men and treated with dihydrotestosterone (DHT) with or without androgen receptor (AR) antagonist, hydroxyflutamide, in vitro. DHT treatment enhanced AR-mediated proliferation, migration and tubulogenesis of EEPCs and OECs in a dose-dependent manner. Furthermore, DHT augmented EPC sensitivity to extracellular stimulation by vascular endothelial growth factor (VEGF) via increased surface VEGF receptor expression and AKT activation. In vivo, xenotransplantation of DHT pretreated human EPCs augmented blood flow recovery and angiogenesis in BALB/c nude male mice, compared to mice receiving untreated EPCs, following hindlimb ischemia. In particular, DHT pretreated human OECs exhibited higher reparative potential than EEPCs in augmenting post-ischemic blood flow recovery in mice. Furthermore, whole blood was collected from the coronary sinus of men with single vessel coronary artery disease (CAD) who underwent elective percutaneous intervention (n=23). Coronary collateralization was assessed using the collateral flow index. Serum testosterone and EPC levels were measured. In men with CAD, circulating testosterone was positively associated with the extent of coronary collateralization and the levels of OECs. In conclusion, androgens enhance EPC function and promote neovascularization after ischemia in mice and are associated with coronary collateralization in men

内皮祖细胞（EPCs）在血管新生中扮演着至关重要的角色，并与心血管健康结局的改善密切相关。尽管已知男性中雄激素水平与心血管死亡率之间存在明确的负相关关系，但雄激素在内皮祖细胞功能中的作用尚未完全明了。在本研究中，我们探讨了雄激素对两种内皮祖细胞亚群——早期内皮祖细胞（EEPCs）和晚期增殖内皮祖细胞（OECs）——的影响及其与冠状动脉侧支循环的关系。EEPCs和OECs从年轻健康男性的外周血中分离出来，并在体外用二氢睾酮（DHT）处理，同时或不与雄激素受体（AR）拮抗剂羟氟他汀联合使用。DHT处理以剂量依赖性方式增强了EEPCs和OECs的AR介导的增殖、迁移和管状生成。此外，DHT通过增加表面VEGF受体表达和AKT激活，增强了内皮祖细胞对细胞外刺激因子血管内皮生长因子（VEGF）的敏感性。在体内，与接受未经处理的EPCs的 BALB/c裸鼠相比，预先用DHT处理的EPCs的异种移植增强了后肢缺血后血流通畅恢复和血管生成。特别是，预先用DHT处理的OECs在增强小鼠缺血后血流通畅恢复方面显示出比EEPCs更高的修复潜力。此外，从接受选择性经皮冠状动脉介入治疗（n=23）的单支冠状动脉疾病（CAD）男性的冠状动脉窦中收集了全血。使用侧支血流指数评估冠状动脉侧支循环。测量了血清睾酮和内皮祖细胞水平。在CAD男性中，循环睾酮与冠状动脉侧支循环的程度和OECs水平呈正相关。总之，雄激素增强了内皮祖细胞的功能，并在小鼠缺血后促进了血管新生，与男性的冠状动脉侧支循环相关。