Role of Adiponectin in Reversal of Age-related Vascular Dysfunction

脂联素在逆转年龄相关血管功能障碍中的作用

• 批准号: 10566303
• 负责人: JUDY M DELP
• 金额: $ 52.09万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10566303
• 关键词: Acute; Adjuvant; Aerobic Exercise; Age; Aging; Agonist; Arteries; Biomedical Research; Blood; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular system; Ceramides; Coronary; Development; Disease; Elderly; Elements; Endothelium; Exercise; Functional disorder; Goals; Impairment; Inflammation; Knock-out; Longevity; Microvascular Dysfunction; Mus; Myocardium; Organ; Phenotype; Prevention; Proteins; Rattus; Reporting; Research Priority; Resistance; Risk Factors; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Smooth Muscle; Sphingosine; Structure; Testing; Training; Vascular Diseases; Vascular Smooth Muscle; Vascular remodeling; Vasomotor; Work; adiponectin; age related; aged; antagonist; arterial remodeling; blood pressure regulation; cardiac vasculature; cardiovascular effects; endothelial dysfunction; exercise training; gain of function; improved; loss of function; middle age; mimetics; novel; pharmacologic; promote resilience; protective effect; receptor; resilience; response; sedentary; senescence; therapeutic target; young adult

Aging is a primary risk factor for development of cardiovascular dysfunction and disease. The hallmarks of vascular aging are endothelial dysfunction, development of a synthetic, atherosclerotic phenotype in smooth muscle, and arterial inflammation and stiffening. We have shown that aerobic exercise training can mitigate or reverse age-related vascular dysfunction and adverse arterial remodeling; however, the cellular signals that contribute to the ability of exercise training to promote macro- and microvascular resiliency remain unidentified. Similarly, the mechanisms whereby exercise training reverses age- related vascular dysfunction remain unknown. Reduced circulating adiponectin has been associated with the adverse vascular changes that occur with advancing age; however, a role for adiponectin in age- related vascular dysfunction has not been demonstrated. We have reported that circulating adiponectin levels increase in response to late-life exercise training; however, a direct role for adiponectin signaling in reversal of age-related vascular dysfunction by exercise training has not been demonstrated. We propose to test a central hypothesis that 1) loss of adiponectin is a critical contributor to age- related vascular dysfunction and adverse arterial remodeling, and 2) adiponectin contributes to the ability of exercise training to promote vascular resiliency and reverse age-related vascular dysfunction and age-related adverse vascular remodeling. We propose to study sedentary and exercise trained mice, across the murine lifespan, to determine 1) the impact of loss- and gain-of-function of adiponectin on ceramide/sphingosine signaling in the endothelium of the microvasculature of the heart and skeletal muscle, 2) the impact of loss- and gain-of-function of adiponectin on development of a senescence-associated synthetic phenotype in vascular smooth muscle and contractile dysfunction the microvasculature of the heart and skeletal muscle, and 3) the impact of loss- and gain-of-function of adiponectin on remodeling of large arteries. Results from the proposed work will increase our understanding of the role of adiponectin in age-related vascular dysfunction and exercise training-induced reversal of age-related vascular dysfunction. A top biomedical research priority is to identify strategies which promote vascular resiliency with advancing age or which reverse age-related vascular dysfunction. The proposed work could identify 1) components of the adiponectin signaling pathway that could be targeted for prevention of age-related vascular dysfunction, and 2) novel exercise mimetics that could be employed for 1) promotion of vascular resiliency across the lifespan, and/or 2) reversal of age-related vascular dysfunction.

衰老是发展心血管功能障碍和疾病的主要危险因素。标志 血管衰老是内皮功能障碍，在合成，动脉粥样硬化表型的发展 平滑肌和动脉炎症和僵硬。我们已经表明有氧运动训练 可以减轻或逆转与年龄有关的血管功能障碍和不良动脉重塑；但是， 有助于运动训练促进宏观和微血管的能力的细胞信号 弹性仍然不明。同样，运动训练扭转年龄的机制 - 相关的血管功能障碍仍然未知。减少的循环脂联素与 随着年龄的增长而发生的不良血管变化；但是，脂联素在年龄中的作用 - 尚未证明相关的血管功能障碍。我们报道了循环脂联素 对后期运动训练的响应水平增加；但是，脂联素信号的直接作用 在逆转与年龄有关的血管功能障碍中，尚未证明锻炼训练。我们 提议检验一个中心假设，即1）脂联素的丧失是年龄的关键因素 相关的血管功能障碍和不良动脉重塑，2）脂联素有助于 运动训练促进血管弹性和反向年龄相关的血管的能力 功能障碍和与年龄相关的不良血管重塑。我们建议研究久坐和 运动训练的小鼠，穿过鼠生的寿命，以确定1）损失和功能收益的影响 神经酰胺/鞘氨醇信号传导的脂联素 和骨骼肌，2）脂联素的损失和功能损益对发展的影响 血管平滑肌和收缩功能障碍中衰老相关的合成表型 心脏和骨骼肌的微脉管系统，3） 大动脉重塑时脂联素。拟议工作的结果将增加我们的 了解脂联素在与年龄有关的血管功能障碍和运动训练引起的作用 与年龄有关的血管功能障碍的逆转。生物医学研究的重点是确定策略 随着年龄的增长或与年龄相关的血管功能障碍，可以促进血管弹性。 拟议的工作可以识别1）可能是脂联素信号通路的组件 针对预防与年龄相关的血管功能障碍的针对性，以及2）可能是新颖的运动模仿物 使用1）促进整个寿命的血管弹性，/或2）与年龄有关的逆转 血管功能障碍。