Division of Vascular Surgery, University of Michigan, Ann Arbor, MI.
J Surg Res. 2014 Jan;186(1):467-74. doi: 10.1016/j.jss.2013.07.050. Epub 2013 Aug 18.
Estrogen receptor alpha (ERα) has been identified in the vessel wall, offering vasoprotective effects when upregulated. Estrogens are known to mediate the inflammatory milieu, and inflammation has long been associated with abdominal aortic aneurysm (AAA) formation. Therefore, it is theorized that increased estrogen receptor in females contributes to their relative resistance to AAAs. The objective of this study was to determine gender differences in ERα levels during experimental AAA formation.
Infrarenal aortas of male and female C57 mice (n = 18 and n = 16, respectively) were infused with 0.4% elastase. Diameters were measured at days 0 and 14. Aortic messenger RNA expression of ERα was determined on day 3 by reverse transcription-polymerase chain reaction, whereas ERα protein levels were measured via Western blot. Immunohistochemistry using rabbit antibody for ERα was performed on day 14 samples and quantified. Zymography was done for matrix metalloproteinases (MMP)2 and 9 activity levels. Samples of human AAAs were collected and Western blot performed. Data were compared for significance using a student t-test.
Infrarenal aortic diameter increased in elastase-perfused males (ME) by 80% at 14 days after perfusion, whereas females (FE) increased by only 35% (P = 0.0012). FE had ×10 greater ERα messenger RNA expression compared with ME at day 3 (P = 0.003). Similarly, ERα protein levels were 100% higher in FE compared with those in ME on day 14 (P = 0.035). ERα protein levels were 80% higher in female human patients with AAA than those in their male counterparts (P = 0.029). ERα visualized via immunohistochemistry was 1.5 fold higher in FE than ME (P = 0.029). MMP2 and 9 activity levels were decreased in female compared with male aortas.
This study demonstrates an increase in aortic wall ERα in females compared with males that correlates inversely with MMP activity and AAA formation. These findings, coupled with observations that exogenous estrogen inhibits AAA formation in males, further suggest that estrogen supplementation may be important to prevent AAA formation and growth.
雌激素受体 α（ERα）已在血管壁中被发现，当它被上调时，会产生血管保护作用。雌激素被认为可以调节炎症环境，而炎症长期以来一直与腹主动脉瘤（AAA）的形成有关。因此，人们推测女性体内雌激素受体的增加有助于她们相对抵抗 AAA。本研究旨在确定在实验性 AAA 形成过程中 ERα 水平的性别差异。
雄性和雌性 C57 小鼠的肾下主动脉（n = 18 和 n = 16）分别用 0.4%弹性蛋白酶灌注。在第 0 天和第 14 天测量直径。第 3 天通过逆转录-聚合酶链反应测定 ERα 的主动脉信使 RNA 表达，通过 Western blot 测定 ERα 蛋白水平。第 14 天样本进行 ERα 兔抗体免疫组织化学检测并进行量化。进行基质金属蛋白酶（MMP）2 和 9 活性水平的酶谱分析。收集人 AAA 样本并进行 Western blot。使用学生 t 检验比较数据的显著性。
弹性蛋白酶灌注后雄性（ME）肾下主动脉直径在 14 天增加了 80%，而雌性（FE）仅增加了 35%（P = 0.0012）。FE 在第 3 天的 ERα 信使 RNA 表达比 ME 高 10 倍（P = 0.003）。同样，在第 14 天，FE 的 ERα 蛋白水平比 ME 高 100%（P = 0.035）。女性 AAA 患者的 ERα 蛋白水平比男性患者高 80%（P = 0.029）。通过免疫组织化学观察到，FE 的 ERα 比 ME 高 1.5 倍（P = 0.029）。与雄性主动脉相比，雌性主动脉的 MMP2 和 9 活性水平降低。
本研究表明，与男性相比，女性主动脉壁 ERα 增加，与 MMP 活性和 AAA 形成呈负相关。这些发现，加上外源性雌激素抑制男性 AAA 形成的观察结果，进一步表明雌激素补充可能对预防 AAA 形成和生长很重要。
