Role of endogenous endothelin in endothelial dysfunction in murine model of systemic sclerosis: tight skin mice 1.
Systemic sclerosis (SSc) is a systemic inflammatory disorder, resulting in severe vascular dysfunction. The endothelin (ET) system has vasoconstrictor and profibrotic properties and has been shown to be activated in SSc. ET antagonists are currently used in SSc-related pulmonary arterial hypertension, but the endothelial impact of ET antagonists remains less known in SSc. We thus assessed the effects of the dual ET(A)-ET(B) antagonist, bosentan, on endothelial dysfunction in a murine model of SSc, the heterozygous tight-skin mice 1 (TSK1(+)). Six-week-old TSK1(+) were either untreated or treated for 6 weeks with bosentan (100 mg/kg/day), and compared with controls. Endothelial function was evaluated in isolated mesenteric resistance arteries, using a small vessel myograph. TSK1(+) displayed endothelial dysfunction, as shown by a decreased response of mesenteric arteries to acetylcholine, especially in the presence of L-nitro-arginine methyl ester (L-NAME), corresponding to NO-independent, prostaglandin-mediated relaxation. The NO-independent relaxation was partially restored in bosentan-treated TSK1(+), and this was abolished by a cyclo-oxygenase inhibitor. Therefore, the murine model of SSc, TSK1(+) exhibits severe endothelial dysfunction of peripheral resistance arteries. The ET antagonist bosentan prevents endothelial alterations, suggesting a major role of ET in the adverse vascular effects of SSc.
Richard
Vincent
V
Inserm U644 & Rouen University Hospital, Institute for Biomedical Research and IFRMP 23, University of Rouen, Rouen, France. vincent.richard@univ-rouen.fr
Solans
Violaine
V
Favre
Julie
J
Henry
Jean-Paul
JP
Lallemand
Françoise
F
Thuillez
Christian
C
Marie
Isabelle
I
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000077300:Bosentan; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009206:Myocardium / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D013449:Sulfonamides / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D011453:Prostaglandins; D017466:Receptors, Endothelin; D013449:Sulfonamides; D014665:Vasodilator Agents; D004008:Diclofenac; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; D000077300:Bosentan; D019331:NG-Nitroarginine Methyl Ester