The cardiovascular system is a major determinant of the body's oxidative metabolism and aerobic capacity; thus, successful cardiovascular aging is critical to maintenance of an active, independent lifestyle in elderly individuals. Aging of the cardiovascular system results in progressive endothelial dysfunction that is associated with increased risk for cardiovascular disease and a loss of skeletal muscle performance. The endothelial dysfunction present in skeletal muscle resistance arteries of aged rats results primarily from reduced nitric oxide (NO) signaling;however, the effects of age on cellular mechanisms that regulate NO signaling remain to be determined. Recent evidence indicates that the availability of tetrahydrobiopterin (BH4), a necessary cofactor in NO production, is decreased in skeletal muscle resistance arteries of aged rats. Inadequate availability of BH4 can result in biochemical uncoupling of endothelial nitric oxide synthase (eNOS) and reduced synthesis of NO. Furthermore, uncoupled eNOS produces superoxide anion (021 a reactive oxygen species which can limit NO signaling and contribute to cellular damage. The overarching goals of this proposal are 1) to determine whether aging results in uncoupling of eNOS and reduction of bioavailable NO in skeletal muscle resistance arteries, and 2) to determine whether interventional strategies, including aerobic exercise training, can reverse age-related deficiencies in BH4 availability and uncoupling of eNOS, increasing NO bioavailability in skeletal muscle resistance arteries.
In Aim 1 NO and O2- will be measured directly to determine whether aging produces uncoupling of eNOS in resistance arteries from rat soleus muscle leading to reduced NO bioavailability, and increased production of cytotoxic O2-.
In Aim 2, endothelium-specific adenoviral gene transfer will be used to determine whether restoration of BH4 availability by overexpression of GTP cyclohydrolase (GTPCH) reverses age-related uncoupling of eNOS, increasing NO bioavailability and reducing O2- in soleus muscle resistance arteries. shRNAi knockdown of GTPCH will also be used to reduce BH4 availability and promote eNOS uncoupling in soleus muscle resistance arteries. The purpose of Aim 3 is to determine whether chronic aerobic exercise training reduces oxidant stress and increases GTPCH expression thereby increasing BH4 availability and reversing age-related uncoupling of eNOS and NO bioavailability in resistance arteries from rat soleus muscle. These studies will increase our understanding of mechanisms that contribute to age-related endothelial dysfunction in resistance vasculature of skeletal muscle and indicate whether specific interventions designed to improve BH4 availability can ameliorate endothelial dysfunction in old age

Public Health Relevance

The ability of the cardiovascular system to provide blood flow to skeletal muscle is critical to the performance of regular physical activity. In aged individuals, blood flow to exercising skeletal muscle may be limited by dysfunction of the endothelium lining small arteries within the muscle. The proposed studies will increase our understanding of age-induced impairments of the endothelium in skeletal muscle, and investigate possible interventional strategies that may ameliorate endothelial dysfunction in aged skeletal muscle.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Charette, Marc F
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University of Florida
Schools of Medicine
United States
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Muller-Delp, Judy M; Hotta, Kazuki; Chen, Bei et al. (2018) Effects of age and exercise training on coronary microvascular smooth muscle phenotype and function. J Appl Physiol (1985) 124:140-149
Turney, Stephen G; Ahmed, Mostafa; Chandrasekar, Indra et al. (2016) Nerve growth factor stimulates axon outgrowth through negative regulation of growth cone actomyosin restraint of microtubule advance. Mol Biol Cell 27:500-17
Ghosh, Payal; Mora Solis, Fredy R; Dominguez 2nd, James M et al. (2015) Exercise training reverses aging-induced impairment of myogenic constriction in skeletal muscle arterioles. J Appl Physiol (1985) 118:904-11
Hanna, Mina A; Taylor, Curtis R; Chen, Bei et al. (2014) Structural remodeling of coronary resistance arteries: effects of age and exercise training. J Appl Physiol (1985) 117:616-23
Chandrasekar, Indra; Goeckeler, Zoe M; Turney, Stephen G et al. (2014) Nonmuscle myosin II is a critical regulator of clathrin-mediated endocytosis. Traffic 15:418-32
Sindler, Amy L; Reyes, Rafael; Chen, Bei et al. (2013) Age and exercise training alter signaling through reactive oxygen species in the endothelium of skeletal muscle arterioles. J Appl Physiol (1985) 114:681-93
Arnold, Kimberly M; Goeckeler, Zoe M; Wysolmerski, Robert B (2013) Loss of focal adhesion kinase enhances endothelial barrier function and increases focal adhesions. Microcirculation 20:637-49
Muller-Delp, Judy M; Gurovich, Alvaro N; Christou, Demetra D et al. (2012) Redox balance in the aging microcirculation: new friends, new foes, and new clinical directions. Microcirculation 19:19-28
Leblanc, Aj; Chen, B; Dougherty, Pj et al. (2012) Divergent effects of aging and sex on vasoconstriction to endothelin in coronary arterioles. Microcirculation :
Kang, Lori S; Chen, Bei; Reyes, Rafael A et al. (2011) Aging and estrogen alter endothelial reactivity to reactive oxygen species in coronary arterioles. Am J Physiol Heart Circ Physiol 300:H2105-15

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