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（Endothelial progenitor cells, EPCs）在血管新生过程中发挥关键作用，且与良好的心血管结局密切相关。尽管男性体内雄激素水平与心血管死亡率之间已确立明确的负相关关系，但雄激素对内皮祖细胞功能的调控作用尚未完全明晰。本研究探讨了雄激素对两类内皮祖细胞亚群——早期内皮祖细胞（early EPCs, EEPCs）与晚期出芽内皮祖细胞（late outgrowth EPCs, OECs）的影响，及其与冠状动脉侧支循环的关联。研究人员从年轻健康男性的外周血中分离得到EEPCs与OECs，体外分别经二氢睾酮（dihydrotestosterone, DHT）单独或联合雄激素受体（androgen receptor, AR）拮抗剂羟基氟他胺处理。结果显示，DHT可通过雄激素受体介导，以剂量依赖性方式增强EEPCs与OECs的增殖、迁移及管形成能力。此外，DHT可通过提升细胞表面血管内皮生长因子受体表达与AKT活化水平，增强内皮祖细胞对血管内皮生长因子（vascular endothelial growth factor, VEGF）介导的细胞外刺激的敏感性。体内实验中，相较于接受未处理内皮祖细胞的小鼠，经DHT预处理的人内皮祖细胞异种移植至BALB/c裸雄性小鼠后，可显著促进后肢缺血模型小鼠的血流恢复与血管新生。尤为值得注意的是，经DHT预处理的人OECs在增强小鼠缺血后血流恢复方面，展现出较EEPCs更高的修复潜能。本研究同时纳入23例接受择期经皮介入治疗的单支冠状动脉疾病（coronary artery disease, CAD）男性患者，采集其冠状窦全血，通过侧支血流指数评估冠状动脉侧支循环情况，并检测血清睾酮与循环内皮祖细胞水平。结果发现，在冠状动脉疾病男性患者中，循环睾酮水平与冠状动脉侧支循环的丰富程度及晚期出芽内皮祖细胞水平呈正相关。综上，雄激素可增强内皮祖细胞功能，促进小鼠缺血后的血管新生，且与男性患者的冠状动脉侧支循环密切相关。