Vascular Regenerative Cell Exhaustion in Diabetes: Translational Opportunities to Mitigate Cardiometabolic Risk

Ischemic cardiovascular complications remain a major cause of mortality in people with type 2 diabetes (T2D). Individuals with T2D may have a reduced ability to revascularize ischemic, tissues due to abnormal production of circulating provascular progenitor cells. This 'regenerative cell exhaustion' process is intensified by increasing oxidative stress and inflammation and during T2D progression. Chronic exhaustion may be mediated by changes in the bone marrow microenvironment that dysregulate the wingless related integration site network, a central pathway maintaining the progenitor cell pool. Restoration of vascular regenerative cell production by reducing glucotoxicity with contemporary antihyperglycemic agents, by reducing systemic inflammation postbariatric surgery, or by modulating progenitor cell provascular functions using exosomal manipulation, may provide unique approaches for mitigating ischemic disease.