Androgens exert sexually dimorphic effects on angiogenesis: novel insight into the relationship between androgens and cardiovascular disease.
Androgens exert sexually dimorphic effects on angiogenesis: novel insight into the relationship between androgens and cardiovascular disease.
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雄激素对血管生成产生性别二态性影响：对雄激素与心血管疾病之间关系的新见解。
DOI：
10.1038/aja.2011.80
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发表时间：
2011
影响因子：
2.9
通讯作者：
Page,StephanieT
中科院分区：
文献类型：
--
作者：
Rubinow,KatyaB;Amory,JohnK;Page,StephanieT
雄激素暴露对男性心血管疾病（CVD）风险的影响仍然知之甚少。鉴于男性CVD发病率较女性早，历史上认为雄激素会增强男性CVD。然而，越来越多的临床数据挑战了这一假设，并越来越多地暗示低水平的循环睾酮是CVD和死亡率的风险因素。1，2在他们最近发表的报告“A sex-specific role for androgens in angiogenesis”中，3 Sieveking及其同事就雄激素对血管生成和缺血性损伤恢复的影响进行了惊人的观察，这是血管修复的重要组成部分，可能提供一种机制，使雄激素可以发挥保护性心血管作用。此外，这些研究结果在体外和体内模型系统中均具有性别特异性，表明雄激素在调节CVD中具有性二态效应。为了更好地阐明雄激素在CVD中的作用，作者研究了不同雄激素暴露对血管生成的影响，血管生成是缺血性损伤后发生的关键修复过程。虽然雌激素已知调节血管生成，4，5雄激素的类似作用尚未建立。使用非芳香化雄激素双氢睾酮（DHT），研究人员首先检查了雄激素暴露对内皮细胞（EC）迁移的影响，这是血管生成的关键步骤。在男性EC中，DHT赋予了剂量依赖性的迁移增加，重要的是，这种作用被阻断了添加雄激素受体（AR）拮抗剂，表明增加的迁移介导的AR依赖性的方式。DHT处理也增强了雄性EC的增殖和小管形成，血管网络的形成。在AR拮抗剂的存在下，这些作用同样被消除。与这些发现一致，DHT治疗增加了EC产生血管内皮生长因子，血管生成中的关键分子，6和血管内皮生长因子受体2。总之，这些数据令人信服地证明了雄激素在男性内皮细胞中的促血管生成作用，这可能有助于保护男性免受CVD.In形成鲜明对比，来自女性的内皮细胞的DHT治疗没有引起迁移，增殖或小管形成的可比变化。由于这种差异效应可能是雌性EC中AR表达减少的结果，因此作者产生了AR过表达的雌性EC。这种操作增加了女性EC中的小管发生，但在某种程度上与男性EC中所见的相比。因此，这一系列的实验提供了强有力的证据，EC雄激素信号通路的性二型性。这些体外研究结果为采用体内血管生成模型的后续研究提供了基础。在雄性和雌性小鼠中，性腺切除术显著降低了基质胶栓塞血管化。尽管DHT治疗完全挽救了切除卵巢的雄性小鼠的血管生成障碍，但它没有改善切除卵巢的雌性小鼠的血管生成。后肢缺血后产生了类似的结果，这是一种专门评估缺血性损伤后血管生成的血管重建模型。通过多普勒灌注成像评估，
The effects of androgen exposure on cardiovascular disease (CVD) risk in men remain poorly understood. Given the earlier incidence of CVD among men relative to women, androgens historically have been assumed to potentiate CVD in men. However, mounting clinical data challenge this assumption and increasingly implicate low levels of circulating testosterone as a risk factor for CVD and mortality. 1, 2 In their recently published report ‘A sex-specific role for androgens in angiogenesis’, 3 Sieveking and colleagues make striking observations regarding the impact of androgens on angiogenesis and recovery from ischemic injury, important components of vascular repair which might provide a mechanism whereby androgens could exert protective cardiovascular effects. Moreover, these findings were sex-specific in both in vitro and in vivo model systems, suggesting a sexually dimorphic effect of androgens in modulating CVD. In order to better elucidate the role of androgens in CVD, the authors investigated the effects of differential androgen exposure on angiogenesis, a critical reparative process that occurs subsequent to ischemic injury. Whereas estrogens are known to modulate angiogenesis, 4, 5 a comparable role for androgens has yet to be established. Using the nonaromatizable androgen dihydrotestosterone (DHT), the investigators first examined the effects of androgen exposure on endothelial cell (EC) migration, a pivotal step in angiogenesis. In male ECs, DHT conferred a dose-dependent increase in migration, and importantly, this effect was blocked by the addition of an androgen receptor (AR) antagonist, indicating that the increased migration was mediated in an AR-dependent fashion. DHT treatment also potentiated increased male EC proliferation and tubulogenesis, the formation of vascular networks. These effects similarly were abrogated in the presence of the AR antagonist. Consistent with these findings, DHT treatment increased EC production of vascular endothelial growth factor, a pivotal molecule in angiogenesis, 6 and vascular endothelial growth factor receptor 2. In aggregate, these data compelling demonstrate pro-angiogenic effects of androgens in male ECs that might help protect men from CVD.In striking contrast, DHT treatment of ECs derived from females did not induce comparable changes in migration, proliferation, or tubulogenesis. As this differential effect could be a consequence of reduced AR expression in female ECs, the authors generated AR-overexpressing female ECs. This manipulation increased tubulogenesis in female ECs but not to an extent comparable to that seen in male ECs. Thus, this series of experiments offers strong evidence for sexual dimorphism in EC androgen signaling pathways. These in vitro findings provided the basis for follow-up studies that employed in vivo models of angiogenesis. In both male and female mice, gonadectomy significantly reduced Matrigel plug vascularization. Whereas DHT treatment completely rescued this angiogenic impairment in orchidectomized male mice, it conferred no improvement in vascularization in the ovariectomized female mice. Parallel findings were generated after hindlimb ischemia, a model of revascularization that specifically assesses angiogenesis in response to ischemic injury. Through assessment by Doppler perfusion imaging and