Microvascular endothelial dysfunction in type 2 diabetes mellitus

Introduction: Microvascular endothelial dysfunction precedes and predicts major adverse cardiovascular events. Type 2 Diabetes Mellitus (T2DM) dramatically increases the risk of cardiovascular disease (CVD). It is unclear whether T2DM is associated with microvascular endothelial dysfunction and the mechanisms underlying this dysfunction. Flow Mediated Dilation (FMD) elicits vasodilation, which is a barometer of overall vascular health and function. Acetylcholine (ACh) is a pharmacological agonist that also elicits vasodilation. Nitric Oxide (NO) is the primary mediator for vasodilation in healthy arterioles, while hydrogen peroxide (H 2 O 2 ) is the primary mediator for vasodilation in diseased arterioles. We hypothesized that T2DM would be associated with microvascular endothelial dysfunction and that this would be evidenced by a switch in the mechanism of vasodilation from NO to H 2 O 2 . Methods: Human arterioles (< 250 µm) were isolated from healthy (< 2 risk factors) and T2DM adipose tissue samples. L-NAME (100 µM) and Peg-Cat (500 U/mL) were incubated for 30 minutes during vessel pressurization (60 mmHg) to inhibit NOS and H 2 O 2 , respectively. Arterioles were pre-constricted with endothelin-1 to 30-70% of their passive diameters. In response to FMD (5 cmH2O – 100 cmH2O), luminal diameter was recorded in 5-minute intervals. In response to ACh (10-9 log M – 10-4 log M), luminal diameter was recorded in 2-minute intervals. Papaverine (100 µM) was used at the end of each experiment to confirm smooth muscle function and assess maximal vasodilator capacity. Data are expressed as mean±SD and expressed as %maximal dilation (FMD) and EC50 (ACh). Significance was defined as P< 0.05. Results: NOS predominates as the mechanism of vasodilation to FMD and ACh in arterioles from healthy individuals as evidence by a reduction in magnitude of vasodilation in the presence of L-NAME, but not Peg-Cat during FMD (L-NAME: 58±15% vs. Peg-Cat: 75±17%, n=3-8, P< 0.05) and ACh (EC50: control 1.4×10 -7 M, L-NAME 3.1×10 -5 M, PEG-Cat 2.3×10 -6 M; P< 0.05 ). In contrast, PEG-Cat reduced FMD responses in arterioles from T2DM (76±9% vs. 68±16%, n=5–8, P< 0.05), indicating H 2 O 2 -dependent dilation, while ACh responses showed only a modest contribution from L-NAME, and improved sensitivity with PEG-Cat (EC50 Control 6.7×10 -8 M, L-NAME 7.9×10 -7 M, and PEG-Cat 2.8×10 -8 M; P< 0.05). Conclusion: Our data demonstrate NO as the primary mediator of FMD and ACh in healthy arterioles. In T2DM, FMD shifts to H 2 O 2 dependence, while PEG-Cat partially restores ACh sensitivity by mitigating ROS inhibition of NO signaling. Funded by NHLBI 5R00HL161491-04 (WEH) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.