BACKGROUND:Arterial stiffness is a cardiovascular risk factor and dramatically increases as women transition through menopause. The current study assessed whether a mouse model of menopause increases arterial stiffness in a similar manner to aging and whether activation of the G-protein–coupled estrogen receptor could reverse stiffness.METHODS:Female C57Bl/6J mice were ovariectomized at 10 weeks of age or aged to 52 weeks, and some mice were treated with G-protein–coupled estrogen receptor agonists.RESULTS:Ovariectomy and aging increased pulse wave velocity to a similar extent independent of changes in blood pressure. Aging increased carotid wall thickness, while ovariectomy increased material stiffness without altering vascular geometry. RNA-sequencing analysis revealed that ovariectomy downregulated smooth muscle contractile genes. The enantiomerically pure G-protein–coupled estrogen receptor agonist, LNS8801, reversed stiffness in ovariectomy mice to a greater degree than the racemic agonist G-1. In summary, ovariectomy and aging induced arterial stiffening via potentially different mechanisms. Aging was associated with inward remodeling, while ovariectomy-induced material stiffness independent of geometry and a loss of the contractile phenotype.CONCLUSIONS:This study enhances our understanding of the impact of estrogen loss on vascular health in a murine model and warrants further studies to examine the ability of LNS8801 to improve vascular health in menopausal women.

中文翻译：

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卵巢切除术引起的动脉硬化不同于血管老化，可通过 GPER 激活来逆转

背景：动脉僵硬度是心血管危险因素，随着女性进入更年期，动脉僵硬度会急剧增加。目前的研究评估了更年期小鼠模型是否会以与衰老类似的方式增加动脉僵硬度，以及 G 蛋白偶联雌激素受体的激活是否可以逆转僵硬度。 方法：雌性 C57Bl/6J 小鼠在 10 周龄时被切除卵巢，或在 10 周龄时被切除卵巢。年龄至 52 周，一些小鼠接受 G 蛋白偶联雌激素受体激动剂治疗。 结果：卵巢切除术和衰老使脉搏波速度增加到类似程度，且与血压变化无关。衰老会增加颈动脉壁的厚度，而卵巢切除会增加材料的硬度，但不会改变血管的几何形状。 RNA测序分析显示，卵巢切除术下调了平滑肌收缩基因。对映体纯的 G 蛋白偶联雌激素受体激动剂 LNS8801 比外消旋激动剂 G-1 更能逆转卵巢切除小鼠的僵硬度。总之，卵巢切除术和衰老通过潜在不同的机制引起动脉硬化。衰老与向内重塑相关，而卵巢切除术引起的材料硬度与几何形状和收缩表型的丧失无关。 结论：这项研究增强了我们对小鼠模型中雌激素损失对血管健康影响的理解，并值得进一步研究以检验LNS8801 改善更年期女性血管健康的能力。