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 …