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

平滑肌细胞雌激素受体α的性二态性在血管衰老中的作用

• 批准号: 10641912
• 负责人: Jennifer DuPont
• 金额: $ 69.48万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-10 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641912
• 关键词: Age; Aging; Agonist; Aorta; Atomic Force Microscopy; Attenuated; Bilateral; Binding; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Chronic; Clinical; Data; Development; Disease Outcome; EFRAC; Elderly; Estrogen Receptor alpha; Estrogen decline; Estrogens; Female; Fibrosis; Goals; Health; Heart Diseases; Heart failure; Hormone replacement therapy; Human; Hypertension; In Vitro; Isolated systolic hypertension; Knockout Mice; Knowledge; Life; Ligands; Measures; Mediating; Medical; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; Organ; Outcome; Ovariectomy; Pathway interactions; Pattern; Pharmaceutical Preparations; Physiologic pulse; Play; Poly(ADP-ribose) Polymerases; Population; Postmenopause; Premenopause; Procedures; Process; Public Health; Receptor Activation; Receptor Signaling; Regulation; Renin-Angiotensin-Aldosterone System; Risk; Risk Factors; Role; Sex Differences; Small Interfering RNA; Smooth Muscle Myocytes; Stroke; Testing; Tissues; Type 2 Angiotensin II Receptor; Vascular Smooth Muscle; Woman; aged; aging population; arm; arterial stiffness; cardiovascular disorder risk; cardiovascular risk factor; chromatin immunoprecipitation; clinically significant; experience; female sex hormone; gene repression; human female; improved; in vivo; in vivo evaluation; inhibitor; innovation; male; men; middle age; mortality; mouse model; new therapeutic target; novel; preservation; prevent; promoter; receptor; receptor expression; receptor function; sex; sexual dimorphism; therapeutic evaluation; therapeutic target; treatment group

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.

衰老与动脉僵硬度 (AS) 上升有关，动脉僵硬度 (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。老龄化相关疾病的发展 AS 遵循性别二态性发展模式，女性在晚年患上 AS，并且女性有 与动脉硬化相关的 CVD 发生率较高，例如孤立性收缩期高血压和心力衰竭 保留射血分数。导致性别发育差异的分子机制 与衰老相关的 AS 尚不清楚。确定这些机制是一项未满足的医疗需求，具有重大意义 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， 与雄性小鼠相比，雌性小鼠的 AS 发病较晚。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 在血管衰老中的作用尚未明确 定义的。最近的研究表明，未配体的 ERα（不含雌激素的 ERα）可能是 不利于血管健康，并且由于女性雌激素水平随着年龄的增长而下降。进一步深造 支持 ERα/雌激素对聚（ADP-核糖）聚合酶-1 (PARP1) 负调节，并且 PARP1 转录抑制血管紧张素 II 2 型受体 (AT2R)，这是肾素-血管紧张素-的保护臂 醛固酮系统。我们的初步数据表明：1）老年雌性小鼠在后期出现 AS 增加 寿命比男性长； 2) 女性血管 ERα 表达随着年龄的增长而升高，3) 雌激素减少 PARP1 的结合 女性 SMC 中的 AT2R 启动子； 4）老年女性内源性血管平滑肌细胞增强 通过原子力显微镜测量的硬度与老年男性进行比较； 5) 在具有 ERα 的新型小鼠模型中 从平滑肌细胞 (SMC-ERα-KO) 中删除，老年女性和循环雌激素可预防 AS 下降，支持未配体 ERα 在动脉硬化中的作用，并且 6) SMC-ERα-KO 小鼠受到保护 与衰老相关的主动脉 PARP1 增加和 AT2R 减少。我们提出了三个具体目标 测试新的假设，即雌激素介导的 PARP1 抑制可保护年轻女性免受 CVD， 导致 AT2R 活性增强，并且随着年龄的增长，未配体的 SMC-ERα 有助于 通过促进 PARP1 并随后抑制 AT2R 表达而导致动脉硬化 和信号。 SA1 将在体外测试 SMC-ERα 调节人类 PARP-1/AT2R 通路的假设 主动脉平滑肌细胞。 SA2 将测试 SMC-ERα 对 PARP-1/AT2R 的调节有助于性的体内假设 通过利用我们的新型 SMC-ERα-KO 小鼠，除了确定衰老小鼠的 AS 的作用外，还研究了 AS 的差异 我们的新型 SMC-PARP1-KO 小鼠在衰老相关 AS 中的 SMC-PARP1。 SA3将测试治疗潜力 慢性 AT2R 激活和 PARP1 抑制可改善雄性和雌性小鼠中与衰老相关的 AS。 长期目标是确定性别特异性治疗目标，以帮助改善动脉僵硬度和 老龄化人口中的相关CVD结果。