do Nascimento Graciliano R A, Barros Yaskara V R, Wells Amanda K, Khalil Raouf A
Division of Vascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA.
Curr Hypertens Rev. 2009 Nov;5(4):283-306. doi: 10.2174/157340209789587717.
Cardiovascular disease (CVD) is more common in men and postmenopausal women than premenopausal women, suggesting vascular benefits of female sex hormones. Studies on the vasculature have identified estrogen receptors ERα, ERβ and a novel estrogen binding membrane protein GPR30, that mediate genomic and/or non-genomic effects. Estrogen promotes endothelium-dependent relaxation by inducing the production/activity of nitric oxide, prostacyclin, and hyperpolarizing factor, and inhibits the mechanisms of vascular smooth muscle contraction including Ca(2+), protein kinase C, Rho kinase and mitogen-activated protein kinase. Additional effects of estrogen on the cytoskeleton, matrix metalloproteinases and inflammatory factors contribute to vascular remodeling. However, the experimental evidence did not translate into vascular benefits of menopausal hormone therapy (MHT), and the HERS, HERS-II and WHI clinical trials demonstrated adverse cardiovascular events. The discrepancy has been partly related to delayed MHT and potential changes in the vascular ER amount, integrity, affinity, and downstream signaling pathways due to the subjects' age and preexisting CVD. The adverse vascular effects of MHT also highlighted the need of specific modulators of vascular sex hormone receptors. The effectiveness of MHT can be improved by delineating the differences in phramcokinetics and pharmacodynamics of natural, synthetic, and conjugated equine estrogens. Estriol, "hormone bioidenticals" and phytoestrogens are potential estradiol substitutes. The benefits of low dose MHT, and transdermal or vaginal estrogens over oral preparations are being evaluated. Specific ER modulators (SERMs) and ER agonists are being developed to maximize the effects on vascular ERs. Also, the effects of estrogen are being examined in the context of the whole body hormonal environment and the levels of progesterone and androgens. Thus, the experimental vascular benefits of estrogen can be translated to the outcome of MHT in postmenopausal CVD, as more specific modulators of sex hormone receptors become available and are used at the right dose, route of administration and timing, depending on the subject's age and preexisting cardiovascular condition.
心血管疾病（CVD）在男性和绝经后女性中比绝经前女性更常见，这表明女性性激素对血管具有益处。对脉管系统的研究已确定雌激素受体ERα、ERβ以及一种新型雌激素结合膜蛋白GPR30，它们介导基因组和/或非基因组效应。雌激素通过诱导一氧化氮、前列环素和超极化因子的产生/活性来促进内皮依赖性舒张，并抑制血管平滑肌收缩机制，包括细胞内钙离子浓度(Ca(2+))、蛋白激酶C、Rho激酶和丝裂原活化蛋白激酶。雌激素对细胞骨架、基质金属蛋白酶和炎症因子的其他作用有助于血管重塑。然而，实验证据并未转化为绝经激素治疗（MHT）对血管的益处，HERS、HERS-II和WHI临床试验均显示存在不良心血管事件。这种差异部分与MHT延迟以及由于受试者年龄和已患有的CVD导致血管雌激素受体数量、完整性、亲和力和下游信号通路的潜在变化有关。MHT的不良血管效应也凸显了对血管性激素受体特异性调节剂的需求。通过明确天然、合成和结合马雌激素在药代动力学和药效学方面的差异，可以提高MHT的有效性。雌三醇 “激素生物仿制药” 和植物雌激素是潜在的雌二醇替代品。正在评估低剂量MHT以及经皮或阴道雌激素相对于口服制剂的益处。正在研发特异性雌激素受体调节剂（SERM）和雌激素受体激动剂，以最大化对血管雌激素受体的作用。此外，正在全身激素环境以及孕酮和雄激素水平的背景下研究雌激素的作用。因此，随着更特异性的性激素受体调节剂问世，并根据受试者年龄和已有的心血管状况以正确的剂量、给药途径和时机使用，雌激素在实验中对血管的益处可以转化为绝经后CVD患者MHT的治疗效果。
