title: Mechanisms of enhanced vasoconstriction in the mouse model of atherosclerosis: the beneficial effects of sildenafil.
abstract: Sildenafil ameliorates aortic relaxations in apolipoprotein E knockout (apoE) mice. Now, we tested the hypothesis that endothelial dysfunction (ED) in this model is characterized by contractile hyperresponsiveness to phenylephrine (PE) and that this abnormality may be repaired using sildenafil. The aortic rings were evaluated in apoE mice treated with sildenafil (apoE-sil, 40 mg/kg/day) and compared with apoE and wild-type (WT) mice administered with vehicle (veh). The apoE-veh mice exhibited an imbalance of nitric oxide and reactive oxygen species (NO/ROS) levels and an increased maximum response (Rmax, 20%) and sensitivity (7%) to PE, which were not modified by endothelial removal. Under the prostanoids blockade, vasocontraction was decreased more in apoE-veh (-37%) than in WT (-27%) and apoE-sil (-30%) mice. NADPH-oxidase blockade abolished the enhanced contractile responsiveness in apoE-veh (-33%), without effects in WT and apoE-sil groups. The atherosclerotic lesions and the imbalance of NO/ROS were reduced (40%) in apoE-sil mice. In conclusion, ED in apoE mice was characterized by decreased NO-bioavailability and contractile hyperresponsiveness, due to thromboxane and oxidative stress, and was normalized by sildenafil. The beneficial effects of this phosphodiesterase-5 inhibitor on ED and lipid deposition provide new insights for its use as adjuvant in the treatment of atherosclerosis.
authors: Marcos A
authors: MA
authors: Leal
authors: Camille M
authors: CM
authors: Balarini
authors: Ananda T
authors: AT
authors: Dias
authors: Marcella L
authors: ML
authors: Porto
authors: Agata L
authors: AL
authors: Gava
authors: Thiago M C
authors: TM
authors: Pereira
authors: Silvana S
authors: SS
authors: Meyrelles
authors: Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo, Av Marechal Campos 1468, 29042-755 Vitoria, ES, Brazil. evasquez@pq.cnpq.br.
authors: Elisardo C
authors: EC
authors: Vasquez
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D055119:Elastic Modulus / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000187:drug effects; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000068677:Sildenafil Citrate / Q000008:administration & dosage*; D016896:Treatment Outcome; D059289:Vascular Stiffness / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage
chemical_list: D001057:Apolipoproteins E; D058986:Phosphodiesterase 5 Inhibitors; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate