Vascular nitric oxide resistance in type 2 diabetes

Vascular nitric oxide (NO center dot) resistance, manifested by an impaired vasodilator function of NO center dot in both the macro- and microvessels, is a common state in type 2 diabetes (T2D) associated with developing cardiovascular events and death. Here, we summarize experimental and human evidence of vascular NO center dot resistance in T2D and discuss its underlying mechanisms. Human studies indicate a similar to 13-94% decrease in the endothelium (ET)-dependent vascular smooth muscle (VSM) relaxation and a 6-42% reduced response to NO center dot donors, i.e., sodium nitroprusside (SNP) and glyceryl trinitrate (GTN), in patients with T2D. A decreased vascular NO center dot production, NO center dot inactivation, and impaired responsiveness of VSM to NO center dot [occurred due to quenching NO center dot activity, desensitization of its receptor soluble guanylate cyclase (sGC), and/or impairment of its downstream pathway, cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG)] are the known mechanisms underlying the vascular NO center dot resistance in T2D. Hyperglycemia-induced overproduction of reactive oxygen species (ROS) and vascular insulin resistance are key players in this state. Therefore, upregulating vascular NO center dot availability, re-sensitizing or bypassing the non-responsive pathways to NO center dot, and targeting key vascular sources of ROS production may be clinically relevant pharmacological approaches to circumvent T2D-induced vascular NO center dot resistance.