classical monocytes, or of a combination of both injury and hampered tissue repair, remains unclear. Endothelial cells play a crucial role by releasing multiple inflammatory mediators and expressing various adhesion molecules, including VCAM-1. This membrane protein is necessary to anchor leukocytes to the vessel wall and is an established marker of endothelial dysfunction. Renal COX-2 activity is also increased in diabetes and is linked to hyperinfiltration. Consistently with this, we found increased VCAM-1 and COX-2 protein expression in diabetic kidneys, accompanied by massive F4/80+iNOS+ M1 macrophage infiltration, and in human endothelial cells exposed to HG, in which monocyte adhesion is enhanced. Interestingly, SILD PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19755711 reduced VCAM-1 expression in mouse tissues and human endothelial cells, lowering monocyte adhesion via TIE2, suggesting that an intact TIE2 receptor is both necessary and sufficient to protect the endothelium. In addition to the emerging evidence supporting the role of PDE5is as inflammation modulators, we characterized, for the first time, the composition of macrophage infiltration and demonstrated a defective recruitment of a specific M2 subset in response to hyperglycemia. The pro-angiogenic tissue macrophages identified here are highly reminiscent of the M2-like pro-angiogenic TEMs that we have described in tumors, developing organs and regenerating tissues. We found that TEM reduction was associated with specific tissue damage and reduced overall survival of STZ mice. Interestingly, we also found that PDE5 inhibition both restores TEMs and prevent pro-inflammatory circulating monocyte expansion triggered by hyperglycemic stress. It is worth noting that our data reveal a specific hyperglycemia-associated reduction in TEMs rather than a global reduction in the total number of MRC-1+ M2 macrophages. The effects of PDE5i thus appear to be specific to a distinct, but relevant, part of the inflammatory process. Long term observation could be of particular 480-44-4 supplier interest to address adaptive changes to chronic inflammatory status. In this respect, previous clinical trials from our group support the use of PDE5i in preventing end-organ complications of diabetes. The improved survival in the current 14 / 17 PDE5 Inhibition Restores M2 Macrophages in Diabetic Mice experimental model is consistent with several others reporting tissue protection from PDE5. In this scenario, TEMs could also serve as a new, robust PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19755667 and accessible marker to monitor vascular complications in diabetes. Future work is awaited to provide more information on monocyte function abnormalities as potential targets to improve the diagnosis and treatment of vascular disorders in diabetes. Acknowledgments The authors thank Fabrizio Padula, Stefania De Grossi for technical assistance at SapienzaUniversity of Roma, Sergio Chiandotto and Daniela Fiore for help with animal treatments and discussion of the results and Marie-Hlne Hayles for revision of the English text. ~~ ~~