Abstract 85: Low-grade Inflammation Participates on the Enhanced Vasoconstriction to the Endogenous Endothelin-1 in Small Vessels From Obese Patients

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Objective: Obesity is characterized by vascular low-grade inflammation, with an augmented endogenous endothelin(ET)-1-mediated vasoconstriction (VC) and a blunted tonic nitric oxid(NO)-mediated relaxation (VD). We evaluated whether TNF-α, localized in the vascular wall and in perivascular adipocytes (PVA), contributes to the VC induced by endogenous ET-1 and whether this action is mediated by an effect on tonic NO release in small resistance arteries from obese patients (Ob) and controls (Ctrl). Method: Sample of visceral fat were obtained in 14 Ob (BMI:42.1±3.7) and 14 Ctrl (BMI:25.4±3.6), matched for metabolic profile and blood pressure values, undergoing laparoscopic surgical procedure. Small arteries were investigated on a pressurized micromyograph. Endogenous ET-1 was assessed by vascular response to BQ-123. TNF-α and NO were assessed by Infliximab (IFX) and L-NAME, respectively. Gene and protein expression of TNF-α, ET-1 and ETA receptors were determined by RT-PCR (gene/reference) and IHC (AU) on arterial wall and in PVA. Results: In Ctrl, L-NAME-induced VC (15.5±0.6%) was not affected by IFX (15.1±0.4%). In contrast, Ob showed a blunted VC to L-NAME (6.0±0.7%; P<0.01 vs Ctrl) which was potentiated (P<0.01) by IFX (12.5±0.8%). In Ob, the VD to BQ-123 (47.0±1.5%) was attenuated (P<0.01) by IFX (29.1±2.4%) and not affected by L-NAME (43,3±0.6%). During IFX co-infusion, L-NAME further reduced the VD to BQ-123 (19.4±3.0%; P<0.01 vs BQ-123+IFX). In Ctrl, VD to BQ-123 was blunted (26.3±1.3%; P<0.01 vs Ob), not affected by IFX (24.1±0.6%) and significantly reduced by L-NAME (12.3±1.1%). Ob showed a significant overexpression of TNF-α respect to Ctrl, either at the level of arterial wall (24.9±19.6 vs 2.8±2.5 AU, P<0.001) or in PVA (2.9±1.8 vs 1.2±0.7 gene/reference, P<0.005). These results were paralleled by a higher arterial expression of ET-1 (45.8±10.3 vs 24.3±15.0 AU, P<0.01) and ETA receptors (69.4±6.0 vs 9.6±2.8 AU, P<0.001) in Ob vs Ctrl. Conclusion: Small vessels of Ob show an enhanced ETA-mediated VC and a blunted NO-mediated VD. An excess of vascular and perivascular TNF-α, coupled with an increased expression of ET-1 and ETA in the vasculature of Ob, contributes to the enhanced ET-1-mediated VC tone partly by an impairment of tonic NO release.