Online_Appendix_R1.pdf (341.44 kB)

Inhibition of SGLT-2 rescues bone marrow cell traffic for vascular repair. Role of glucose control and ketogenesis

Download (341.44 kB)
posted on 26.04.2021, 22:16 by Mattia Albiero, Serena Tedesco, Francesco Ivan Amendolagine, Marianna D’Anna, Ludovica Migliozzi, Gaia Zuccolotto, Antonio Rosato, Roberta Cappellari, Angelo Avogaro, Gian Paolo Fadini
The mechanisms whereby sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve cardiovascular outcomes in people with diabetes are incompletely understood. Recent studies show that SGLT2i may increase the levels of circulating cells with vascular regenerative capacity, at least in part by lowering glycemia. Here, we used mice with streptozotocin-induced diabetes treated with the SGLT2i dapagliflozin at a dose that reduced glucose levels by ~20%. Dapagliflozin improved the diabetes-associated defect of hematopoietic stem cell mobilization after stimulation with G-CSF. Dapagliflozin rescued the traffic of bone marrow (BM)-derived cells to injured carotid arteries and improved endothelial healing in diabetic mice. Defective homing of CD49d+ granulocytes was causally linked with impaired endothelial repair and was reversed by dapagliflozin. The effects of dapagliflozin were mimicked by a similar extent of glucose reduction achieved with insulin therapy, and by a ketone drink that artificially elevated β-hydroxybutyrate. Inhibition of endothelial repair by resident cells using the CXCR4 antagonist AMD3100 did not abolish the vascular effect of dapagliflozin, indirectly supporting that endothelial healing by dapagliflozin was mediated by recruitment of circulating cells. In summary, we show that dapagliflozin improved the traffic of BM-derived hematopoietic cells to the site of vascular injury, providing a hitherto unappreciated mechanism of vascular protection.


This study was supported by grants from: University of Padova (DOR), The ministry of University and Education (PRIN projects 2015ZTT5KB and 201793XZ5A), and AstraZeneca (NCR-17-12732).