Heal Thyself: SGLT2 Inhibition Limits Regenerative Cell Exhaustion and Heals Damaged Vessels

Chronic metabolic dysfunction as a result of type 2 diabetes (T2D) increases susceptibility to the development of ischemic cardiovascular disease (CVD) (1). The search for therapies to improve cardiovascular health in individuals afflicted with T2D has led to the discovery and utilization of a novel class of glucose-lowering drugs called sodium– glucose cotransporter 2 inhibitors (SGLT2i). Located in the proximal tubule of the kidney, the SGLT2 receptor directs the reuptake of glucose and sodium into the circulation (2,3). Inhibition of this pathway results in glucosuria/natriuresis and represents a novel metabolic mechanism to reduce hyperglycemia during T2D. Several randomized clinical trials in people with and without diabetes have now established a critical role for SGLT2i in the reduction of cardiovascular and cardiorenal events (4,5). While direct myocardial and indirect metabolic effects have been proposed to explain these benefits, recent data suggest that SGLT2 inhibition stimulates vascular repair via increased trafficking of bone marrow–derived provascular progenitor cells essential for vessel regeneration (6–9). In this issue of Diabetes, Albiero et al. (10) definitively demonstrate that despite low levels of expression of SGLT2 on hematopoietic cells, SGLT2 inhibition with dapagliflozin improved endothelial repair through enhanced recruitment of hematopoietic stem/progenitor cell (HSPC) progeny from the bone marrow (BM) to the site of vessel injury. In concept, circulating HSPC represent critical intermediates in blood vessel homeostasis via the coordination of angiogenic, arteriogenic, and vasculogenic processes (11). Seminal contributions by the Fadini group and others have previously established a significant depletion in circulating provascular HSPC during T2D, which contributes to vascular dysfunction and increased risk of CVD (12–14). To assess the role of HSPC following SGLT2i treatment, streptozotocin (STZ)-treated mice were administered dapagliflozin or vehicle for 2 weeks at a dose that decreased hyperglycemia by 20% and did not alter LKS (Lin /c-kit/Sca-1) progenitor cell frequency in the BM (10). Albiero et al. first revealed that dapagliflozin administration reduced the frequency of SIGLEC-1–expressing (CD169) macrophages in the BM of STZ-treated mice by 70% (10). Although the role of CD169 macrophages in the M1 versus M2 polarization spectrum is unclear, elevated CD169 macrophage content in the BM of patients with diabetes acts to retain HSPC in the BM niche and prevents HSPC mobilization (15). Indeed, dapagliflozin treatment in STZ-treated mice normalized BM CD169 macrophage content and partially rescued the HSPC mobilization defect in response to granulocyte colonystimulating factor (10). Next, the authors examined the effect of improved HSPC mobilization on the induction of carotid artery wound healing. Remarkably, re-endothelialization after denudation injury was decreased 10-fold in hyperglycemic mice, and endothelial healing was significantly improved after dapagliflozin treatment (10). Elegant experiments, involving carotid artery denudation in chimeric mice reconstituted with green fluorescent protein–positive (GFP) BM cells, effectively traced GFP HSPC progeny localized to the site of carotid injury. Reduced recruitment of GFP cells to the site of carotid injury in STZ-treated diabetic chimeric mice was reversed by dapagliflozin treatment (10). What was the phenotype of these regenerative GFP cells? Multiparametric flow cytometry analyses demonstrated GFP/LKS cells were rarely detected (<0.1) at the site of injury, whereas mature monocyte and neutrophil