Role of Adiponectin in Reversal of Age-related Vascular Dysfunction

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.

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.