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Diabetes. 2016 Nov;65(11):3505-3515. Epub 2016 Aug 5.

Enhanced Integrin α4β1-Mediated Adhesion Contributes to a Mobilization Defect of Endothelial Progenitor Cells in Diabetes.

Author information

1
Diabetes and Obesity Center, University of Louisville, Louisville, KY.
2
Department of Physiology, University of Louisville, Louisville, KY.
3
Department of Medicine, University of California, San Diego, San Diego, CA.
4
Diabetes and Obesity Center, University of Louisville, Louisville, KY teotoo01@louisville.edu.

Abstract

Diabetes is associated with a deficit of circulating endothelial progenitor cells (EPCs), which has been attributed to their defective mobilization from the bone marrow. The basis for this mobilization defect is not completely understood, and we sought to determine if hyperglycemic conditions enhanced EPC adhesion. We found that culturing EPCs in high glucose media increased adhesion to bone marrow stromal cells. This enhanced adhesion was associated with decreased expression of protein kinase A regulatory subunit 1β (PRKAR1β), activation of protein kinase A (PKA), and phosphorylation of α4-integrin on serine 988. This potentiated adhesion was reversed by treatment with a PKA inhibitor, overexpression of PRKAR1β, or expression of a phosphorylation-defective α4-integrin variant (α4[S988A]). Using a model of type 1 diabetes, we showed that α4(S988A)-expressing mice have more circulating EPCs than their wild-type counterparts. Moreover, diabetic α4(S988A) mice demonstrate enhanced revascularization after hind limb ischemia. Thus, we have identified a novel signaling mechanism activating PKA in diabetes (downregulation of an inhibitory regulatory subunit) that leads to deficits of circulating EPCs and impaired vascular repair, which could be reversed by α4-integrin mutation.

PMID:
27495221
PMCID:
PMC5079633
DOI:
10.2337/db16-0634
[Indexed for MEDLINE]
Free PMC Article

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