Background/Aims: The atherosclerotic apolipoprotein E-deficient (apoE^-/-) mouse exhibits impaired vasodilation and enhanced vasoconstriction responsiveness. The objectives of this study were: a) to determine the relative contribution of cyclooxygenases (Cox-1 and Cox-2), thromboxane A2 (TXA2) and endothelin-1 (ET-1) to enhancing vascular hyperresponsiveness in this model of atherosclerosis and b) to investigate the beneficial effects of the phosphodiesterase 5 inhibitor sildenafil on this endothelial dysfunction. Methods: Adult male apoE^-/- mice were treated with sildenafil (40 mg/kg/day, for 3 weeks) and compared with non-treated ApoE^-/- and wild-type mice. The beneficial effects of sildenafil on vascular contractile response to phenylephrine (PE) in aortic rings were evaluated before and after incubation with Cox-1 (SC-560) or Cox-2 (NS-398) inhibitors or the TP antagonist SQ-29548, and on contractile responsiveness to ET-1. Results: ApoE^-/- mice exhibited enhanced vasoconstriction to PE (R_max ∼35%, p<0.01), which was prevented by treatment with sildenafil. The enhanced PE-induced contractions were abolished by both Cox-1 inhibition and TP antagonist, but were not modified by Cox-2 inhibition. Aortic rings from ApoE^-/- mice also exhibited enhanced contractions to ET-1 (R_max ∼30%, p<0.01), which were attenuated in sildenafil-treated ApoE^-/- mice. In addition, we observed augmented levels of vascular proinflammatory cytokines in ApoE^-/- mice, which were partially corrected by treatment with sildenafil (IL-6, IL-10/IL-6 ratio and MCP-1). Conclusion: The present data show that the Cox-1/TXA2 pathway prevails over the Cox-2 isoform in the mediation of vascular hypercontractility observed in apoE^-/-mice. The results also show a beneficial effect of sildenafil on this endothelial dysfunction and on the proinflammatory cytokines in atherosclerotic animals, opening new perspectives for the treatment of other endothelium-related cardiovascular abnormalities.

The present study aimed to test the hypothesis that increased sodium concentration affects the migratory phenotype of vascular smooth muscle cells (VSMCs) independently of the haemodynamic factors. Cell migration was evaluated by wound‐healing assay under the following conditions: high sodium (HS, 160 mM) and control (CT, 140 mM). Cell viability was assessed by annexin V and propidium iodide labeling. Cyclooxygenase‐2 (COX‐2) gene expression was analysed by reverse transcription polymerase chain reaction. ERK1/2 phosphorylation was assessed by western blot. Exposure of VSMCs to HS reduced migration, and AT1R blockade prevented this response. HS increased COX‐2 gene expression, and COX‐2 blockade prevented the reduction in VSMC migration induced by HS. HS also increased ERK1/2 phosphorylation, and ERK1/2 inhibition recovered VSMC migration as well as blocked COX‐2 gene expression. The TXA2 receptor blocker, but not the prostacyclin receptor blocker, prevented the HS‐induced VSMCs migration decrease. HS reduces the migration of VSMCs by increasing COX‐2 gene expression via AT1R‐ERK1/2 phosphorylation. In addition, increased COX‐2 by HS seems to modulate the reduction of VSMCs migration by the TXA2 receptor.