Abstract 14043: Enhanced Integrin α4β1-mediated Adhesion Contributes to a Mobilization Defect of Endothelial Progenitor Cells in Diabetes
While previous studies have identified a deficit of circulating endothelial progenitor cells (EPCs) in diabetic conditions (diabetic “mobilopathy”), the basis for these deficits are not completely understood. To model the adhesive properties of EPCs in diabetic conditions, we cultured these cells in high glucose and found that they had stronger adhesion to bone marrow stromal cells. This enhanced adhesion was associated with decreased expression of protein kinase A regulatory subunit 1β (PRKAR1β), consequent activation of protein kinase A (PKA), and phosphorylation of the α4 integrin on serine 988. The potentiating effects of high glucose on adhesion were mimicked by direct PKA activation and reversed by treatment with a PKA inhibitor, overexpression of PRKAR1β or expression of a phosphorylation-defective α4 integrin (α4-S988A). Using the STZ model of type I diabetes, we show that α4-S988A-expressing mice have more circulating EPCs than do their wild type counterparts (2.6 ± 0.5 fold). Furthermore, the diabetic α4-S988A mice demonstrate enhanced revascularization (1.50 ± 0.3 fold vs. WT) and tissue repair after hind limb ischemia. Thus, hyperglycemic conditions potentiate the adhesion of EPCs to bone marrow stromal cells which results in an in vivo mobilization defect. Mutational reversal of this increased adhesion liberates EPCs and promotes re-endothelialization in ischemic tissues, suggesting a potential therapeutic target to treat diabetic vascular complications.
Author Disclosures: T. O'Toole: None. W. Abplanalp: None. D. Conklin: None. J. Cantor: None. M. Ginsberg: None. A. Bhatnagar: None.
- © 2015 by American Heart Association, Inc.