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.

衰老与动脉硬化（AS）升高有关，AS是心血管疾病（CVD）的独立危险因素。