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:
- 金额:$ 69.48万
- 依托单位:
- 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:
- 关键词:AgeAgingAgonistAortaAtomic Force MicroscopyAttenuatedBilateralBindingBlood VesselsCardiovascular DiseasesCardiovascular systemChronicClinicalDataDevelopmentDisease OutcomeEFRACElderlyEstrogen Receptor alphaEstrogen declineEstrogensFemaleFibrosisGoalsHealthHeart DiseasesHeart failureHormone replacement therapyHumanHypertensionIn VitroIsolated systolic hypertensionKnockout MiceKnowledgeLifeLigandsMeasuresMediatingMedicalMolecularMorbidity - disease rateMusMyocardial InfarctionOrganOutcomeOvariectomyPathway interactionsPatternPharmaceutical PreparationsPhysiologic pulsePlayPoly(ADP-ribose) PolymerasesPopulationPostmenopausePremenopauseProceduresProcessPublic HealthReceptor ActivationReceptor SignalingRegulationRenin-Angiotensin-Aldosterone SystemRiskRisk FactorsRoleSex DifferencesSmall Interfering RNASmooth Muscle MyocytesStrokeTestingTissuesType 2 Angiotensin II ReceptorVascular Smooth MuscleWomanagedaging populationarmarterial stiffnesscardiovascular disorder riskcardiovascular risk factorchromatin immunoprecipitationclinically significantexperiencefemale sex hormonegene repressionhuman femaleimprovedin vivoin vivo evaluationinhibitorinnovationmalemenmiddle agemortalitymouse modelnew therapeutic targetnovelpreservationpreventpromoterreceptorreceptor expressionreceptor functionsexsexual dimorphismtherapeutic evaluationtherapeutic targettreatment 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.
衰老与动脉硬化(AS)升高有关,AS是心血管疾病(CVD)的独立危险因素。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jennifer DuPont其他文献
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