Endothelial progenitor cell (EPC) dysfunction may contribute to vascular dysfunction in type 2 diabetes (T2DM) and aging because EPCs are progenitor cells that participate in vascular growth and repair. EPCs may be dysregulated in older age and T2DM by reduced mobilization from bone marrow and impaired function once in the circulation. My preliminary data suggest that aerobic exercise training may increase EPC and vascular function in T2DM, but that the effects may be reduced in older age. This study tests the hypothesis that reduced EPC mobilization and function adversely affect vascular function in T2DM, and that and that there are age-associated differences in the effects of AEX training on EPC mobilization and function in T2DM, which will affect AEX-induced changes in angiogenesis and endothelial vasoreactivity. This will be accomplished by specific aims that 1) Determine the effects of 6-month aerobic exercise training on EPC number and EPC mobilization factor expression in older subjects with T2DM compared middle-aged T2DM subjects and normal controls;and 2) Determine the effects of 6-month aerobic exercise training on mechanisms regulating EPC function and migration in older subjects with T2DM compared middle-aged T2DM subjects and normal controls. I will study sedentary, overweight/obese (BMI >25 kg/m2), middle-aged (50-65 yrs) and older (65-80 yrs) adults with T2DM and an age- and BMI- matched group of healthy controls. All subjects will be studied before and after 6-months of aerobic exercise training. An acute bout of exercise will be used to assess EPC mobilization at each time point to determine whether EPC mobilization is reduced in older vs. middle-aged T2DM subjects and normal controls, and also whether aerobic exercise training improves EPC mobilization. In the same subjects, ex vivo EPC tube formation, migration, and gene expression will be measured to determine whether specific markers of EPC function are reduced in middle-aged and older T2DM compared to controls and are improved with exercise training. Endothelial vasoreactivity and skeletal muscle capillarization will be measured to determine whether increases in EPC mobilization and function are associated with improved vascular function in T2DM and whether this differs between older and middle-aged T2DM subjects. This mentored, patient-oriented translational research study will provide me with the training to determine mechanisms of EPC dysfunction at the molecular and cellular level, and translate those findings to tissue (skeletal muscle capillarization) and the whole body level (endothelial vasoreactivity). Results of this study will enhance our understanding of EPC and vascular dysfunction and may lead to therapeutic and pharmacologic strategies to reduce vascular dysfunction in T2DM. This Paul B. Beeson Patient-Oriented Career Development Award will allow me to transition to an independent research career and become a leader in translational research in vascular biology in aging and diabetes.

Public Health Relevance

The research project in this K23 BCDA is designed to discover mechanisms underlying endothelial progenitor cell (EPC) and vascular dysfunction in type 2 diabetes and aging. Further, it will determine whether exercise training-induced increases in EPC mobilization contribute to improved vascular function in middle-aged and older adults with type 2 diabetes. The identification of the mechanisms of EPC and vascular dysfunction would have a significant impact on the millions of older Americans with T2DM, as these mechanisms can be targeted for drug discovery or other therapeutic interventions to reduce risk for cardiovascular complications.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZAG1-ZIJ-6 (M1))
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Joseph, Lyndon
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University of Maryland Baltimore
Internal Medicine/Medicine
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United States
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Landers-Ramos, Rian Q; Prior, Steven J (2018) The Microvasculature and Skeletal Muscle Health in Aging. Exerc Sport Sci Rev 46:172-179
Addison, Odessa; Kundi, Rishi; Ryan, Alice S et al. (2018) Clinical relevance of the modified physical performance test versus the short physical performance battery for detecting mobility impairments in older men with peripheral arterial disease. Disabil Rehabil 40:3081-3085
Addison, Odessa; Prior, Steven J; Kundi, Rishi et al. (2018) Sarcopenia in Peripheral Arterial Disease: Prevalence and Effect on Functional Status. Arch Phys Med Rehabil 99:623-628
Blumenthal, Jacob B; Gitterman, Anna; Ryan, Alice S et al. (2017) Effects of Exercise Training and Weight Loss on Plasma Fetuin-A Levels and Insulin Sensitivity in Overweight Older Men. J Diabetes Res 2017:1492581
Addison, Odessa; Ryan, Alice S; Prior, Steven J et al. (2017) Changes in Function After a 6-Month Walking Intervention in Patients With Intermittent Claudication Who Are Obese or Nonobese. J Geriatr Phys Ther 40:190-196
Landers-Ramos, Rian Q; Sapp, Ryan M; VandeWater, Emily et al. (2017) Investigating the extremes of the continuum of paracrine functions in CD34-/CD31+ CACs across diverse populations. Am J Physiol Heart Circ Physiol 312:H162-H172
Kundi, Rishi; Prior, Steven J; Addison, Odessa et al. (2017) Contrast-Enhanced Ultrasound Reveals Exercise-Induced Perfusion Deficits in Claudicants. J Vasc Endovasc Surg 2:
Landers-Ramos, Rian Q; Corrigan, Kelsey J; Guth, Lisa M et al. (2016) Short-term exercise training improves flow-mediated dilation and circulating angiogenic cell number in older sedentary adults. Appl Physiol Nutr Metab 41:832-41
Prior, Steven J; Ryan, Alice S; Blumenthal, Jacob B et al. (2016) Sarcopenia Is Associated With Lower Skeletal Muscle Capillarization and Exercise Capacity in Older Adults. J Gerontol A Biol Sci Med Sci 71:1096-101
Lutz, Andrew H; Blumenthal, Jacob B; Landers-Ramos, Rian Q et al. (2016) Exercise-induced endothelial progenitor cell mobilization is attenuated in impaired glucose tolerance and type 2 diabetes. J Appl Physiol (1985) 121:36-41

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