Role of Adiponectin in Reversal of Age-related Vascular Dysfunction

衰老是心血管功能障碍和疾病发展的主要危险因素。其特点是 血管老化的主要原因是内皮功能障碍，发展为一种合成的动脉粥样硬化表型 肌肉光滑，动脉发炎和僵硬。我们已经证明了有氧运动训练 可以缓解或逆转与年龄相关的血管功能障碍和不利的动脉重构；然而， 有助于运动训练促进大血管和微血管能力的细胞信号 弹性仍未确定。同样，运动训练逆转年龄的机制-- 相关的血管功能障碍仍不清楚。循环中的脂联素减少与 随着年龄的增长而发生的不利的血管变化；然而，脂联素在年龄中的作用- 相关的血管功能障碍尚未得到证实。我们已经报道了循环脂联素 在晚年运动训练中，脂联素的水平升高；然而，脂联素信号的直接作用 在通过运动训练逆转与年龄相关的血管功能障碍方面尚未得到证实。我们 建议检验一个中心假设，即1)脂联素的丢失是年龄的关键因素-- 相关的血管功能障碍和不良的动脉重塑，以及2)脂联素在 运动训练促进血管弹性和逆转年龄相关性血管的能力 功能障碍和年龄相关的不良血管重塑。我们建议研究久坐不动和 运动训练的小鼠，在小鼠的寿命内，确定1)功能丧失和功能获得的影响 脂联素对心脏微血管内皮细胞神经酰胺/鞘氨醇信号转导的影响 和骨骼肌，2)脂联素功能丧失和功能恢复对糖尿病发展的影响。 衰老相关的血管平滑肌合成表型与收缩功能障碍 心脏和骨骼肌的微血管构筑，以及3)功能丧失和功能恢复的影响 脂联素对大动脉重塑的影响。拟议工作的结果将增加我们的 脂联素在增龄性血管功能障碍和运动训练中的作用 逆转与年龄相关的血管功能障碍。生物医学研究的首要任务是确定策略 它们随着年龄的增长而促进血管弹性，或者逆转与年龄相关的血管功能障碍。 这项拟议的工作可以确定1)脂联素信号通路中可能存在的成分 旨在预防与年龄相关的血管功能障碍，以及2)新的运动模拟物，可以 用于1)促进血管在整个寿命内的弹性，和/或2)逆转与年龄相关的 血管功能障碍。

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.