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(AS)增加有关，AS是心血管疾病(CVD)的独立危险因素 这会导致高血压、心脏病发作、中风和最终的器官损伤。老龄化相关疾病的研究进展 下面是一种性发育的二态模式，女性在晚年发育，而女性 动脉僵硬相关的心血管疾病的发生率较高，如单纯的收缩期高血压和心力衰竭 保存的射血分数。儿童发育过程中导致性别差异的分子机制 与衰老相关的AS尚不清楚。确定这些机制是一个未得到满足的医学需求，具有重要的意义 对公共健康的影响。我们已经证明，衰老的小鼠遵循类似的AS发展模式， 与雄鼠相比，雌鼠发病较晚。雌激素及雌激素受体α(ERα) 在绝经前状态下具有保护作用，但雌激素/ERα在血管老化中所起的作用尚未得到 已定义。最近的研究表明，去连接的ERα(不含雌激素的ERα)可能是 对血管健康有害，而且女性的雌激素水平随着年龄的增长而下降。进一步研究 支持ER-α/雌激素负性调节多聚腺苷二磷酸核糖聚合酶-1 转录抑制血管紧张素II 2型受体(AT2R)，肾素-血管紧张素-2的保护臂- 醛固酮系统。我们的初步数据表明：1)随着年龄的增长，雌性小鼠的发育速度加快 2)女性血管ERα表达随年龄增长而升高；3)雌激素降低PARP1的结合 对女性SMC中AT2R启动子的作用；4)老年女性固有的血管平滑肌细胞增强 原子力显微镜测量的僵硬程度与老年男性的比较；5)在带有ERα的新小鼠模型中 从平滑肌细胞(SMC-ERα-KO)中删除，这在老年女性和循环中的雌激素中是被阻止的 下降，支持未连接的ERα在动脉硬化中的作用，6)SMC-ERα-KO小鼠受到保护 随着年龄的增长，主动脉PARP1增加，AT2R减少。我们提出了三个具体目标，以 测试新的假设，即年轻女性通过雌激素介导的PARP1抑制来保护自己免受心血管疾病的影响， 导致AT2R活性增强，并随着年龄的增长，未连接的SMC-ERα有助于 PARP1促进动脉硬化及其对AT2R表达的抑制 和信号。SA1将在体外验证这一假设，即SMC-ERα调节人类PARP-1/AT2R途径 主动脉SMC。SA2将在体内验证SMC-ERα调节PARP-1/AT2R有助于性行为的假设 除了确定SMC-ERα-KO小鼠的作用外，还利用我们新的SMC-ER SMC-KO小鼠研究衰老小鼠AS的差异 SMC-PARP1与我们的新型SMC-PARP1-KO小鼠衰老相关。SA3将测试治疗潜力 慢性AT2R激活和PARP1抑制以改善雄性和雌性小鼠的衰老相关AS。 长期目标是确定针对性别的治疗靶点，以帮助改善动脉僵硬和 老龄化人口中相关的心血管疾病结局。