School of Medical Science, Faculty of Health and Medicine, University of Sydney, Sydney, Australia.
Heart Research Institute, Sydney, Australia.
Endocrinology. 2020 May 1;161(5). doi: 10.1210/endocr/bqaa043.
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 2 subpopulations of EPCs, early EPCs (EEPCs) and late outgrowth EPCs (OECs), and their relationships with coronary collateralization. Early EPCs 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. Dihydrotestosterone 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 postischemic 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) 在血管新生中起着关键作用，并且与改善心血管结局有关。尽管男性的雄激素水平与心血管死亡率之间存在明确的反比关系，但雄激素对 EPC 功能的影响尚未完全阐明。在这项研究中，我们研究了雄激素对 2 种 EPC 亚群（早期 EPCs [EEPCs] 和晚期出芽 EPCs [OECs]）的影响，及其与冠状动脉侧支循环的关系。从年轻健康男性的外周血中分离出早期 EPC 和 OEC，并在体外用二氢睾酮 (DHT) 及其雄激素受体 (AR) 拮抗剂羟基氟他胺处理。DHT 处理以剂量依赖性方式增强了 EEPC 和 OEC 的 AR 介导的增殖、迁移和管腔形成。此外，DHT 通过增加表面血管内皮生长因子 (VEGF) 受体表达和 AKT 激活，增强了 EPC 对血管内皮生长因子 (VEGF) 等细胞外刺激的敏感性。在体内，与接受未处理的 EPC 的小鼠相比，经 DHT 预处理的人 EPC 的异种移植增强了 BALB/c 裸鼠后肢缺血后血流恢复和血管生成。特别是，与 EEPC 相比，DHT 预处理的人 OEC 在增强小鼠缺血后血流恢复方面表现出更高的修复潜力。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）男性的冠状窦采集全血。使用侧支血流指数评估冠状动脉侧支循环。测量血清睾酮和 EPC 水平。在 CAD 男性中，循环睾酮与冠状动脉侧支循环的程度和 OEC 水平呈正相关。总之，雄激素增强了 EPC 的功能，并促进了小鼠缺血后的血管新生，与男性的冠状动脉侧支循环有关。
