Background and aims The hypothesis of this study was that microvascular flow-induced dilation (FID) and acetylcholine-induced dilation (AChID) is impaired in visceral (VAT) compared to subcutaneous adipose tissue (SAT) arterioles in morbidly obese women. Additional aim was to determine the mechanisms contributing to FID and AChID in VAT and SAT arterioles. Methods and results Arterioles were obtained from SAT and VAT biopsies from women (BMI>35 kg/m2) undergoing bariatric surgery. Microvessels were cannulated for reactivity measurements in response to flow (pressure gradients of 10–100 cmH2O) and to acetylcholine (ACh;10−9–10−4 M) with and without Nω-nitro-L-arginine methyl ester (L-NAME), indomethacin (INDO), and PEG-catalase. Nitric oxide (NO)and hydrogen peroxide (H2O2) generation were detected in arterioles by fluorescence microscopy. FID and AChID of arterioles from VAT were reduced compared to SAT arterioles. In SAT arterioles, L-NAME, INDO, and PEG-catalase significantly reduced FID and AChID but had no effect individually on VAT arterioles’ vasodilator reactivity. INDO+L-NAME reduced FID in VAT arterioles. NO-fluorescence was greater in arterioles from SAT compared to VAT arterioles. Vascular H2O2 generation during flow was similar in both VAT and SAT. Conclusion Our results suggest that VAT arterioles display reduced vasodilator reactivity to flow and ACh compared to SAT arterioles, mediated by different regulatory mechanisms in human obesity.

Apolipoprotein E (apoE) is widely expressed in mammalian tissues and one of the important tissue-specific effects is the atheroprotection ascribed to macrophage-derived apoE in the arterial wall. However, underlying mechanisms are not well understood. In this study, using subcellular fractionation, confocal microscopy and co-immunoprecipitation, we demonstrate that macrophage-derived apoE is internalized by endothelial cells and impacts the subcellular distribution/interaction of caveolin-1 and eNOS. Addition of apoE disrupts the heteromeric complex formed between caveolin-1 and eNOS, and increases nitric oxide (NO) production. Sterol and oxysterol enhance endothelial caveolin-1/eNOS interaction and suppress NO production but these effects are reversed by apoE. Silencing endothelial caveolin-1 attenuates apoE induced NO production establishing the importance of Cav-1/eNOS interaction for the increment in endothelial NO for the apoE effect. Consistent with these observations, macrophage-derived apoE significantly improves vasodilation to acetylcholine in resistance arteries isolated from adipose tissue of obese humans. We conclude that macrophage-derived apoE enhances endothelial NO production by disrupting the inhibitory interaction of eNOS with caveolin-1. These results establish a novel mechanism by which apoE modulates endothelial cell function.

Objective: To determine the effect of AT1 receptor antagonism on skin microcirculation and plasma level of thromboxane A₂ (TXA₂). Methods: Healthy women (n=20) maintained 7 days low salt (LS) diet (intake <40 mmol Na/day) without (LS) or together with 50 mg/per day of losartan (a selective AT1 receptor inhibitor) (LS diet+losartan group). Laser Doppler flowmetry (LDF) measurements of changes in post occlusive hyperemic blood flow, plasma concentration of stable TXA₂ metabolite thromboxane B₂ (TXB₂) and plasma renin activity (PRA) aldosterone concentration, electrolytes (Na⁺, K⁺), as well as blood pressure and heart rate were determined before and after study protocols. Results: PRA and aldosterone increased significantly after 7 days of both LS diet and LS diet+losartan. LS diet or LS diet+losartan administrations had no significant effect on post-occlusion hyperemia While there was no change in TXB₂ after LS diet TXB₂ significantly increased after one week of LS+losartan compared to control levels (cTXB2 pg/mL control 101±80 vs. LS diet+losartan 190±116, p<0.05). Conclusion: These data suggest that inhibition of AT1 receptors could lead to activation of AT2 receptors, which maintain hyperemia, despite the increased level of vasoconstrictor TXA₂. These findings also suggest an important role of crosstalk between renin-angiotensin system (RAS) and arachidonic acid metabolites in the regulation of microcirculation under physiological conditions.

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