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Download fileInhibition of SGLT-2 rescues bone marrow cell traffic for vascular repair. Role of glucose control and ketogenesis
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posted on 2021-04-26, 22:16 authored by Mattia Albiero, Serena Tedesco, Francesco Ivan Amendolagine, Marianna D’Anna, Ludovica Migliozzi, Gaia Zuccolotto, Antonio Rosato, Roberta Cappellari, Angelo Avogaro, Gian Paolo FadiniThe 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.