Formation of STAT5/PPAR{gamma} 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.