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Type 2 Diabetes Mellitus and Ex Vivo High Glucose Exposure Induce a Switch in the Mechanism of Microvascular Dilation That is Rescued by Activation of Autophagy

Flow‐mediated dilation, (FMD) manifests as arteriolar vasodilation in response to shear stress in an endothelium‐dependent manner. Nitric oxide (NO) is the primary mediator of FMD in health, while hydrogen peroxide (H2O2) predominates in chronic disease states such as coronary artery disease (CAD). We have previously demonstrated that autophagy, a cell recycling process, is critical in mediating the switch in dilator mechanism in CAD. Type 2 Diabetes Mellitus (T2DM) is an independent risk factor in the development of cardiovascular disease, with hyperglycemia a widely‐acknowledged hallmark of the disease. We sought to examine if presence of T2DM or high glucose exposure induce a switch in the mechanism of microvascular dilation to shear stress that is dependent upon autophagic flux. Human arterioles from discarded adipose tissue from T2DM subjects and healthy controls were isolated and prepared for videomicroscopy. Arterioles from healthy subjects were exposed to ex vivo high glucose (HG; 20 mM D‐glucose) and exposed to an autophagy activator (trehalose, 10 mM). Shear‐induced autophagic flux was measured using Lysotracker Red DND‐99 in the presence and absence of the lysosomal inhibitor bafilomycin A (BAFA1). Internal diameters were measured after graded increases in intraluminal pressure gradients (flow) in the presence/absence of a NOS inhibitor (L‐NAME; 100μM) or H2O2 scavenger (Peg‐Catalase, Peg‐Cat; 500 units/mL). Data are expressed as fold change in fluorescence (shear‐induced autophagy) and % maximal dilation (FMD). Significance was defined as P<0.05.