Date on Master's Thesis/Doctoral Dissertation

12-2015

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Physiology and Biophysics

Degree Program

Physiology and Biophysics, PhD

Committee Chair

Bhatnagar, Aruni

Committee Co-Chair (if applicable)

Joshua, Irving

Committee Member

Joshua, Irving

Committee Member

D'souza, Stanley

Committee Member

Schuschke, Dale A.

Committee Member

Hill, Bradford G.

Committee Member

O'Toole, Timothy

Author's Keywords

endothelial progenitor cells; diabetes; cardiovascular disease; endothelial dysfunction

Abstract

Circulating angiogenic stem cells (CACs) are rare cells found in peripheral blood that have been shown to contribute to endothelial repair and new blood vessel formation. These cells could be biomarkers and/or therapeutic targets for the assessment and prevention of cardiovascular disease (CVD), which is the leading cause of mortality globally and in the United States. Diabetes is an independent risk factor for CVD, and there are inconsistent reports on the role of CACs in diabetic vasculopathy. To study this further we tested the hypothesis that diabetes depletes circulating levels of CACs, due to hyperglycemia or insulin resistance and that CAC depletion contributes to vascular dysfunction associated with diabetes. It was further proposed that in subjects with diabetes CACs may be dysfunctional. Studies presented here identify one subgroup of CAC, (CAC-3: AC133+/CD34+/CD45dim/CD31+/CD14-), that is reduced in diabetes and whose levels are negatively associated with hyperglycemia and endothelial function. Furthermore we found that increased plasma levels of soluble ICAM-1 are also associated with decreased CAC-3 levels and VEGFR2 surface expression. Our results also show that subjects with diabetes have CACs with decreased adhesive and proliferative capacity. These studies identify the specific CAC phenotypes that are affected by diabetes and suggest that CAC levels are a robust index of long-term glycemic control and that their levels reflect hyperglycemia rather than insulin levels. These studies also suggest that CAC levels may be monitored by bedside assessment of endothelial function.

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