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

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.

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.

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.

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.