CaMKII Antagonism Improves Vascular Dysfunction in the Visceral Adipose Microvasculature of Obese Subjects.

Objective: We have previously demonstrated angiogenic impairment, inflammation, and endothelial vasomotor dysfunction in the visceral adipose vasculature of obese individuals. Here, we investigated the role of calcium/calmodulin-dependent protein kinase II (CaMKII) in the regulation of vascular phenotype in the adipose microvasculature.

Methods: Using visceral and subcutaneous fat specimens biopsied from obese subjects (BMI 48 ± 9 kg/m², age 38 ± 11 years), we examined the effect of CaMKII antagonism on acetylcholine-mediated, endothelium-dependent vasodilation of isolated arterioles using videomicroscopy and studied angiogenic capillary sprouting capacity ex vivo.

Results: Pharmacological inhibition of CaMKII with KN-93 improved endothelium-dependent vasodilation of isolated visceral arterioles by 3-fold (p < 0.001 vs. control) and increased visceral fat sprouting capacity by 2.5-fold (p < 0.001). Inhibition of endothelial nitric oxide synthase with N(ω)-nitro-l-arginine methyl ester blunted KN-93-induced improvements in vasodilation and angiogenesis, suggesting dependence on increased nitric oxide bioavailability. KN-93 had no effect on subcutaneous angiogenic capacity, which exhibited preserved angiogenic growth compared to visceral fat. KN-93 exposure was associated with reduced reactive oxygen species generation and decreased vascular gene expression of JUN, NFAT5, and CAMKII signaling components.

Conclusion: Our findings suggest that CaMKII signaling may negatively modulate microvascular function, contribute to increased oxidative stress, and pro-inflammation observed in the visceral adipose microenvironment in obesity.