RT Journal Article
T1 Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE-/- Mice
A1 Leal, Marcos A.S.
A1 Dias, Ananda T.
A1 Porto, Marcela L.
A1 Brun, Bruna F.
A1 Gava, Agata L.
A1 Meyrelles, Silvana S.
A1 Gil Longo, José
A1 Campos Toimil, Manuel
A1 Pereira, Thiago M.C.
A1 Vasques, Elisardo C.
K1 Atherosclerosis
K1 Endothelial dysfunction
K1 Oxidative stress
K1 TXA2
K1 ET-1
K1 Cyclooxygenase
AB 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 (Rmax ∼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 (Rmax ∼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
PB Karger
SN 1015-8987
YR 2018
FD 2018-01
LK http://hdl.handle.net/10347/16777
UL http://hdl.handle.net/10347/16777
LA eng
NO Leal, M., Dias, A., Porto, M., Brun, B., Gava, A., & Meyrelles, S. et al. (2017). Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE<sup>-/-</sup> Mice. Cellular Physiology And Biochemistry, 44(5), 1796-1809. http://dx.doi.org/10.1159/000485817
NO This research was supported by National Council for the Development of Science and Technology (CNPq) (Ref. Grants #303001/2015-1, #307584/2015-1, #445736/2014-3 and # 445080/2014-0) and the State Foundation for Science and Technology (Fapes) (Ref. Grant Universal 2014 Proc #67597483/15). The funding bodies had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript
DS Minerva
RD 28 abr 2026