| First Author | Abplanalp WT | Year | 2016 |
| Journal | Diabetes | Volume | 65 |
| Issue | 11 | Pages | 3505-3515 |
| PubMed ID | 27495221 | Mgi Jnum | J:249385 |
| Mgi Id | MGI:5923432 | Doi | 10.2337/db16-0634 |
| Citation | Abplanalp WT, et al. (2016) Enhanced Integrin alpha4beta1-Mediated Adhesion Contributes to a Mobilization Defect of Endothelial Progenitor Cells in Diabetes. Diabetes 65(11):3505-3515 |
| abstractText | 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 1beta (PRKAR1beta), activation of protein kinase A (PKA), and phosphorylation of alpha4-integrin on serine 988. This potentiated adhesion was reversed by treatment with a PKA inhibitor, overexpression of PRKAR1beta, or expression of a phosphorylation-defective alpha4-integrin variant (alpha4[S988A]). Using a model of type 1 diabetes, we showed that alpha4(S988A)-expressing mice have more circulating EPCs than their wild-type counterparts. Moreover, diabetic alpha4(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 alpha4-integrin mutation. |
