Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility (M.R.B.), Vascular Biology and Hypertension Program, Division of Cardiovascular Disease (D.X., Y-F.C., S.O., F.G.H.) and the Division of Clinical Immunology and Rheumatology (A.J.S.), Department of Medicine, and the School of Medicine (A.K.), The University of Alabama at Birmingham, Birmingham, AL 35294, USA, Section of Cardiology, Birmingham Veteran's Administration Medical Center, Birmingham, AL 35294, USA (F.G.H.).
Arterioscler Thromb Vasc Biol. 2014 Jul;34(7):1477-1485. doi: 10.1161/ATVBAHA.114.303629. Epub 2014 May 29.
17β-Estradiol (E2) offers cardiovascular protection in young female animals and postmenopausal women. In contrast, randomized trials of menopausal hormones performed in older women have shown harm or no cardiovascular benefit. We hypothesize that E2 effects on vascular inflammation are age dependent.
Young (10 weeks) and aged (52 weeks) female C57BL/6 mice were used as source for primary cultures of bone marrow-derived macrophages (BMMs) and vascular smooth muscle cells (VSMCs). E2 pretreatment of cells derived from young mice attenuated C-reactive protein (CRP)-induced expression of inflammatory mediators. In contrast, E2 pretreatment of cells from aged mice did not alter (BMMs) or paradoxically exaggerated (VSMCs) inflammatory mediator response to CRP. Using E2 receptor (ER) knockout mice, we demonstrated that E2 regulates inflammatory response to CRP in BMMs via ERα and in VSMCs via ERβ. BMMs derived from aged (versus young) mice expressed significantly less ERα mRNA and protein. A selective ligand of the novel ER GPR30 reproduced the E2 effects in BMMs and VSMCs. Unlike in young mice, E2 did not reduce neointima formation in ligated carotid arteries of aged CRP transgenic mice.
E2 attenuates inflammatory response to CRP in BMMs and VSMCs derived from young but not aged mice and reduces neointima formation in injured carotid arteries of young but not aged CRP transgenic mice. ERα expression in BMMs is greatly diminished with aging. These data suggest that vasoprotective effects of E2 are age dependent and may explain the vasotoxic effects of E2 seen in clinical trials of postmenopausal women.
17β-雌二醇（E2）为年轻雌性动物和绝经后妇女提供心血管保护。相比之下，在老年女性中进行的绝经激素随机试验显示出危害或没有心血管益处。我们假设 E2 对血管炎症的影响是年龄依赖性的。
年轻（10 周）和年老（52 周）的雌性 C57BL/6 小鼠被用作骨髓来源的巨噬细胞（BMM）和血管平滑肌细胞（VSMC）的原代培养的来源。E2 预处理来自年轻小鼠的细胞可减轻 C 反应蛋白（CRP）诱导的炎症介质表达。相比之下，E2 预处理来自老年小鼠的细胞不会改变（BMM）或相反地夸大（VSMC）对 CRP 的炎症介质反应。使用 E2 受体（ER）敲除小鼠，我们证明了 E2 通过 ERα调节 BMM 中 CRP 诱导的炎症反应，通过 ERβ调节 VSMC 中的炎症反应。来自老年（与年轻）小鼠的 BMM 表达的 ERα mRNA 和蛋白明显减少。新型 ER GPR30 的选择性配体在 BMM 和 VSMC 中重现了 E2 的作用。与年轻小鼠不同，E2 不能减少 CRP 转基因老年结扎颈动脉中的新生内膜形成。
E2 可减弱年轻而非老年小鼠来源的 BMM 和 VSMC 中 CRP 诱导的炎症反应，并减少年轻而非老年 CRP 转基因小鼠损伤颈动脉中的新生内膜形成。BMM 中的 ERα 表达随年龄增长而大大减少。这些数据表明，E2 的血管保护作用是年龄依赖性的，这可能解释了绝经后妇女临床试验中 E2 的血管毒性作用。
