Inhibition of SGLT2 Rescues Bone Marrow Cell Traffic for Vascular Repair: Role of Glucose Control and Ketogenesis

Mattia Albiero, Serena Tedesco, Francesco Ivan Amendolagine, Marianna D'Anna, Ludovica Migliozzi, Gaia Zuccolotto, Antonio Rosato, Roberta Cappellari, Angelo Avogaro, Gian Paolo Fadini

Research output: Contribution to journalArticlepeer-review


The mechanisms by which 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. In this study, 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 granulocyte colony-stimulating factor. 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.

Original languageEnglish
Pages (from-to)1767-1779
Number of pages13
Issue number8
Publication statusPublished - Aug 2021


  • Animals
  • Benzhydryl Compounds/pharmacology
  • Blood Glucose/metabolism
  • Bone Marrow Cells/drug effects
  • Diabetes Mellitus, Experimental/metabolism
  • Glucosides/pharmacology
  • Hematopoietic Stem Cells/drug effects
  • Human Umbilical Vein Endothelial Cells/drug effects
  • Humans
  • Mice
  • Sodium-Glucose Transporter 2 Inhibitors/pharmacology


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