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 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 promoter enabled us to demonstrate that STAT5 transcriptional activity controls PPAR expression. Moreover, FACS analysis, coimmunoprecipitation experiments, and ChIP assay revealed that a STAT5/PPAR transcriptional complex controls cyclin D1 expression and CAC progression into the cell-cycle. Conversely, PPAR agonists, by preventing the expression of STAT5 and the formation of the STAT5/PPAR 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 transcriptional complex.

Conclusions—Our data identify the STAT5/PPAR heterodimers as landmark of CAC expansion and provide evidences for a mechanism that partially rescues CAC bioavailability in diabetic setting.