Endothelial Progenitor Cell Dysfunction in Diabetes Mellitus Type-2: Focus on Nitric Oxide System

Abstract

Diabetes mellitus type-2 (DM-2) is a global epidemic that is associated with a large economic burden, an increased risk of cardiovascular disease, poor outcomes as a result of vascular occlusion, and premature mortality. The clinical hallmark of DM-2 is hyperglycemia – with an etiology which involves genetic, environmental, and behavioral elements. Vascular endothelial function is impaired in DM-2. The underlying cause for the clinical severity of vascular occlusive disease in DM-2 patients has been partly attributed to impaired collateral vessel development due to altered function of mature endothelial cells (Abaci et al., 1999). Furthermore, increasing evidence suggest that new blood-vessel formation in adults may also involve bone marrow (BM)-derived endothelial progenitor cells (EPCs) (Asahara et al., 1997). The ability of DM-2 patients to develop coronary collaterals is diminished due to a diabetes-associated reduction in EPC count and an impairment of EPC mobilization (Lambiase et al., 2004). The deleterious effects of hyperglycemia on the vasculature are further exacerbated in DM-2 patients with elevated plasma lipid levels (Kanter et al., 2007). Several studies have shown that hyperglycemia or oxidized low-density lipoprotein (oxLDL) can reduce EPC count as well as impair EPC migration and proliferation by exerting harmful effects on the phosphatidylinositol-3 kinase (PI 3-K)/protein kinase B (PKB/Akt)/endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) signaling cascade (Callaghan et al., 2005; Chen et al., 2007; Krankel et al., 2005; Ma et al., 2006). This review presents and discusses the underlying metabolic alterations to the molecular mechanisms that are responsible for decreased EPC count and functionality in DM-2. The involvement of the NO system in this phenomenon is highlighted.