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

基本信息

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
项目类别：
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

项目摘要

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.

衰老与动脉刚度上升有关（AS），这是心血管疾病的独立危险因素（CVD）这会导致高血压，心脏病发作，中风和最终器官损伤。衰老相关的发展如下以下是性二态性发展模式，女性在以后的生活中，妇女有较高的动脉刚度相关CVD的发生率，例如分离的收缩压和心力衰竭保留的射血分数。有助于性别差异发展的分子机制与衰老相关的目前尚不清楚。这些机制的确定是未满足的医疗需求公共卫生的影响。我们已经表明，老化小鼠遵循AS的类似开发模式与雄性相比，雌性小鼠经历了晚期发作。雌激素和雌激素受体α（ERα）在绝经前的状态下受到保护，但是雌激素/ERα在血管衰老中起作用的作用尚未定义。最近的研究表明，非配体的ERα（没有雌激素的ERα）可能是由于血管健康有害，并且由于女性随着年龄的增长而下降。进一步的研究支持ERα/雌激素对聚（ADP-核糖）聚合酶1（PARP1）进行负面调节，并且PARP1 转录反映了血管紧张素II类型2受体（AT2R），这是肾素 - 血管紧张素的受保护臂醛固酮系统。我们的初步数据表明：1）随着较晚的生活比男性； 2）血管ERα表达在女性中随着年龄的增长而上升，3）雌激素降低了PARP1的结合向女性SMC的AT2R启动子； 4）老年女性的内在血管平滑肌细胞增强了与古老的男性相比，通过原子力显微镜测量的刚度； 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，如旧雌性和循环雌激素所预防的下降，支持在动脉僵硬中非配合ERα的作用，6）SMC-ERα-KO小鼠受到保护衰老相关的主动脉PARP1的增加并减少AT2R。我们提出了三个具体目标测试新的假设，即通过雌激素介导的PARP1抑制，使年轻女性免受CVD的保护，导致AT2R活性增强，并且随着年龄的增长，无配合的SMC-ERα有助于通过促进PARP1和AT2R表达的结果抑制动脉僵硬的发展和信号。 SA1将在体外测试SMC-ERα调节人类PARP-1/AT2R途径的假设主动脉SMC。 SA2将测试体内假设，即SMC-ERα调节PARP-1/AT2R有助于性通过使用我们的新型SMC-ERα-KO小鼠，除了确定的作用外与我们的新型SMC-PARP1-KO小鼠相关的衰老相关的SMC-PARP1。 SA3将测试治疗潜力慢性AT2R激活和PARP1抑制以改善与雄性和雌性小鼠相关的衰老相关。长期目标是确定特定性别的治疗靶标，以帮助改善动脉僵硬和老龄化人口中相关的CVD结果。