Formation of STAT5/PPARγ Transcriptional Complex Modulates Angiogenic Cell Bioavailability in Diabetes

Objective-Circulating angiogenic cells (CACs) expansion is a multistage process requiring sequential activation of transcriptional factors, including STAT5. STAT5, in concert with peroxisome proliferator-activated receptors (PPARs), seems to induce discrete biological responses in different tissues. In the present study we investigated the role of STAT5 and PPAR gamma in regulating CAC expansion in normal and diabetic settings. Methods and Results-Normal and diabetic CACs were used. siRNA technology, EMSA, and chromatin immunoprecipitation (ChIP) assay as well as site-directed mutagenesis of the STAT5 response element in the PPAR gamma promoter enabled us to demonstrate that STAT5 transcriptional activity controls PPAR gamma expression. Moreover, FACS analysis, coimmunoprecipitation experiments, and ChIP assay revealed that a STAT5/PPAR gamma transcriptional complex controls cyclin D1 expression and CAC progression into the cell-cycle. Conversely, PPAR gamma agonists, by preventing the expression of STAT5 and the formation of the STAT5/PPAR gamma heterodimeric complex failed to promote CAC expansion. Finally, we demonstrated that diabetic CAC functional capability can be recovered by molecules able to activate the STAT5/PPAR gamma transcriptional complex. Conclusions-Our data identify the STAT5/PPAR gamma heterodimers as landmark of CAC expansion and provide evidences for a mechanism that partially rescues CAC bioavailability in diabetic setting. (Arterioscler Thromb Vasc Biol. 2009; 29: 114-120.)