Lam Yuen Ting, Lecce Laura, Tan Joanne T M, Bursill Christina A, Handelsman David J, Ng Martin K C
The Heart Research Institute (Y.T.L., L.L., J.T.M.T., C.A.B., M.K.C.N.), Newtown, Sydney, New South Wales 2042, Australia; Sydney Medical School (Y.T.L., L.L., J.T.M.T., C.A.B., M.K.C.N.), The University of Sydney, Sydney, New South Wales 2006, Australia; ANZAC Research Institute (D.J.H.), The University of Sydney, Concord Hospital, Sydney, New South Wales 2139, Australia; and Department of Cardiology (M.K.C.N.), Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales 2050, Australia.
Endocrinology. 2016 Dec;157(12):4853-4864. doi: 10.1210/en.2016-1301. Epub 2016 Oct 18.
Increasing evidence indicates that androgens regulate ischemia-induced neovascularization. However, the role of genomic androgen action mediated by androgen receptor (AR), a ligand-activated nuclear transcription factor, remains poorly understood. Using an AR knockout (KO) mouse strain that contains a transcriptionally inactive AR (ARKO), we examined the role of AR genomic function in modulating androgen-mediated augmentation of ischemia-induced neovascularization. Castrated wild-type (AR) and ARKO mice were implanted with 5α-dihydrotestosterone (DHT) or placebo pellets after hindlimb ischemia (HLI). DHT modulation of angiogenesis and vasculogenesis, key processes for vascular repair and regeneration, was examined. Laser Doppler perfusion imaging revealed that DHT enhanced blood flow recovery in AR mice post-HLI. In AR mice, DHT enhanced angiogenesis by down-regulating prolyl hydroxylase 2 and augmenting hypoxia-inducible factor-1α (HIF-1α) levels in the ischemic tissues post-HLI. DHT also enhanced the production and mobilization of Sca1+/CXCR4+ progenitor cells in the bone marrow (BM) and circulating blood, respectively, in AR mice. By contrast, DHT-mediated enhancement of blood flow recovery was abrogated in ARKO mice. DHT modulation of HIF-1α expression was attenuated in ARKO mice. DHT-induced HIF-1α transcriptional activity and DHT-augmented paracrine-mediated endothelial cell tubule formation were attenuated in fibroblasts isolated from ARKO mice in vitro. Furthermore, DHT-induced augmentation of Sca1+/CXCR4+ progenitor cell production and mobilization was absent in ARKO mice post-HLI. BM transplantation revealed that ischemia-induced mobilization of circulating progenitor cells was abolished in recipients of ARKO BM. Together, these results indicate that androgen-mediated augmentation of ischemia-induced neovascularization is dependent on genomic AR transcriptional activation.
越来越多的证据表明，雄激素可调节缺血诱导的新生血管形成。然而，由雄激素受体（AR）介导的基因组雄激素作用的角色，即一种配体激活的核转录因子，仍知之甚少。我们使用一种包含转录失活AR的AR基因敲除（KO）小鼠品系（ARKO），研究了AR基因组功能在调节雄激素介导的缺血诱导新生血管形成增强中的作用。对去势的野生型（AR）和ARKO小鼠进行后肢缺血（HLI）处理后，植入5α-双氢睾酮（DHT）或安慰剂药丸。检测了DHT对血管生成和血管发生（血管修复和再生的关键过程）的调节作用。激光多普勒灌注成像显示，DHT可增强HLI后AR小鼠的血流恢复。在AR小鼠中，DHT通过下调脯氨酰羟化酶2并提高HLI后缺血组织中的缺氧诱导因子-1α（HIF-1α）水平来增强血管生成。DHT还分别增强了AR小鼠骨髓（BM）和循环血液中Sca1+/CXCR4+祖细胞的产生和动员。相比之下，ARKO小鼠中DHT介导的血流恢复增强作用被消除。ARKO小鼠中DHT对HIF-1α表达的调节作用减弱。在体外从ARKO小鼠分离的成纤维细胞中，DHT诱导的HIF-1α转录活性和DHT增强的旁分泌介导的内皮细胞小管形成减弱。此外，HLI后ARKO小鼠中不存在DHT诱导的Sca1+/CXCR4+祖细胞产生和动员的增强。BM移植显示，ARKO BM受体中缺血诱导的循环祖细胞动员被消除。总之，这些结果表明雄激素介导的缺血诱导新生血管形成增强依赖于基因组AR转录激活。
