The sexually dimorphic role of smooth muscle cell estrogen receptor alpha in vascular aging

衰老与动脉僵硬度（AS）升高相关，AS是心血管疾病（CVD）的独立危险因素 导致高血压心脏病中风和终末器官损伤老龄化相关的发展 AS遵循性二态性发展模式，女性在晚年发展为AS，女性 动脉硬化相关CVD的发生率较高，如单纯收缩期高血压和心力衰竭， 射血分数正常在发育过程中导致性别差异的分子机制 与年龄相关的AS尚不清楚。这些机制的确定是一个未满足的医疗需求， 公共卫生影响。我们已经证明，衰老小鼠遵循类似的AS发展模式， 与雄性相比，雌性小鼠出现AS的晚发。雌激素和雌激素受体α（ERα） 在绝经前状态下具有保护作用，但雌激素/ERα在血管老化中的作用尚未被证实。 定义了最近的研究表明，未配体的ERα（不存在雌激素的ERα）可能是 这对血管健康有害，并且由于女性雌激素水平随着年龄的增长而下降。进一步研究 支持ERα/雌激素负调节聚（ADP-核糖）聚合酶-1（PARP 1），PARP 1 在转录上抑制血管紧张素II 2型受体（AT 2 R），这是一个保护性的手臂， 醛固酮系统我们的初步数据表明：1）衰老的雌性小鼠在较晚的时间内发展为AS增加， 2）女性血管ERα表达随年龄增长而增加，3）雌激素减少PARP 1的结合 女性SMC中AT 2 R启动子; 4）老年女性具有增强的内在血管平滑肌细胞 与老年男性相比，通过原子力显微镜测量硬度; 5）在ERα的新型小鼠模型中 从平滑肌细胞中删除（SMC-ERα-KO），在老年女性和循环雌激素中预防AS 下降，支持未配体ERα在动脉硬化中的作用，6）SMC-ERα-KO小鼠受到保护， 与年龄相关的主动脉PARP 1增加和AT 2 R减少。我们提出了三个具体目标， 检验新的假设，即年轻女性通过雌激素介导的PARP 1抑制而免受CVD的影响， 导致AT 2 R活性增强，随着年龄的增长，未配体的SMC-ERα有助于 通过促进PARP 1和随后抑制AT 2 R表达发展动脉硬化 和信号。SA 1将在体外验证SMC-ERα调节人PARP-1/AT 2 R通路的假设 主动脉SMC。SA 2将检验SMC-ERα调节PARP-1/AT 2 R有助于性别的体内假设 通过使用我们的新型SMC-ERα-KO小鼠，除了确定 SMC-PARP 1在我们的新型SMC-PARP 1-KO小鼠的衰老相关AS中的作用。SA 3将测试治疗潜力 慢性AT 2 R激活和PARP 1抑制，以改善雄性和雌性小鼠的衰老相关AS。 长期目标是确定性别特异性治疗靶点，以帮助改善动脉僵硬度和动脉硬化。 老年人群中相关的CVD结局。

Aging is associated with rising arterial stiffness (AS), an independent risk factor for cardiovascular disease (CVD) that leads to hypertension, heart attack, stroke, and end organ damage. The development of aging-associated AS follows a sexually dimorphic pattern of development with women developing AS later in life and women have higher rates of arterial stiffness-associated CVD such as isolated systolic hypertension and heart failure with preserved ejection fraction. The molecular mechanisms that contribute to sex differences in the development of aging-associated AS are unclear. Determination of these mechanisms is an unmet medical need with significant public health implications. We have shown that aging mice follow a similar pattern of development of AS, with female mice experiencing a late onset of AS compared to males. Estrogen and estrogen receptor alpha (ERα) are protective in the premenopausal state, yet the role that estrogen/ERα plays in vascular aging has not been defined. Recent studies have suggested that unliganded ERα (ERα without the presence of estrogen) may be detrimental to vascular health and due to the declining levels of estrogen in females with age. Further studies support that ERα/estrogen negatively regulate poly (ADP-ribose) polymerase-1 (PARP1) and that PARP1 transcriptionally represses the angiotensin II type 2 receptor (AT2R), a protective arm of the renin-angiotensin- aldosterone system. Our preliminary data demonstrate that: 1) aging female mice develop increased AS later in life than males; 2) vascular ERα expression rises with age in females, 3) estrogen reduces the binding of PARP1 to the AT2R promoter in female SMC; 4) elderly females have enhanced intrinsic vascular smooth muscle cell stiffness measured by atomic force microscopy compared to elderly males; 5) in a novel mouse model with ERα deleted from smooth muscle cell (SMC-ERα-KO), AS is prevented in old females and circulating estrogen declines, supporting a role for unliganded ERα in arterial stiffening and 6) SMC-ERα-KO mice are protected from the aging-associated increase in aortic PARP1 and decrease in AT2R. We have proposed three specific aims to test the novel hypothesis that young females are protected from CVD by estrogen--mediated inhibition of PARP1, resulting in enhanced AT2R activity and that with advancing age, unliganded SMC-ERα contributes to the development of arterial stiffening via the promotion of PARP1 and consequential inhibition of AT2R expression and signaling. SA1 will test the hypothesis in vitro that SMC-ERα regulates the PARP-1/AT2R pathway in human aortic SMC. SA2 will test the in vivo hypothesis that SMC-ERα regulation of PARP-1/AT2R contributes to sex differences in AS in aging mice by utilizing our novel SMC-ERα-KO mice in addition to determining the role of SMC-PARP1 in aging-associated AS with our novel SMC-PARP1-KO mice. SA3 will test the therapeutic potential of chronic AT2R activation and PARP1 inhibition to ameliorate aging-associated AS in male and female mice. The long-term goal is to identify sex-specific therapeutic targets to aid in improving arterial stiffness and the associated CVD outcomes in the aging population.