Endothelial dysfunction in murine model of systemic sclerosis: tight-skin mice 1.
We conducted this study to analyze endothelial cell function within intact thoracic aorta of the systemic sclerosis murine model, the heterozygous tight-skin mice 1: (i) assessing the distribution and activation intensity of endothelial cells, responsive to endothelium-dependent vasodilators (acetylcholine, adenosine triphosphate, bradykinin, and substance P) and Iloprost, using laser line confocal microscopy in combination with two Ca2+ fluorescent dyes; (ii) evaluating en-dothelium-dependent vasodilator- and Iloprostinduced relaxation, using isometric tension measurement; and (iii) investigating the role of nitric oxide in mediating relaxation to acetylcholine and adenosine triphosphate. The number of activated endothelial cells was significantly lower in heterozygous tight-skin mice 1, compared with controls, for adenosine triphosphate and Iloprost. Maximal increase of Ca2+ fluorescence intensity ratio in activated endothelial cells was decreased for adenosine triphosphate, bradykinin, and Iloprost, in heterozygous tight-skin mice 1. Adenosine triphosphate- and Iloprost-mediated aortic relaxation was further impaired in heterozygous tight-skin mice 1. Finally, aortic relaxation to acetylcholine and adenosine triphosphate was markedly decreased by nitric oxide synthase inhibitor in heterozygous tight-skin mice 1. This study suggests that endothelial cell receptors for endothelium-dependent vasodilators and Iloprost may not be homogeneously distributed or continuously expressed in thoracic aorta of heterozygous tight-skin mice 1, resulting in endothelium-dependent vasodilatation dysfunction. Moreover, because endothelium-dependent relaxation was highly dependent on nitric oxide release in heterozygous tight-skin mice 1, endothelium-dependent relaxation may differ from that of controls by increased production of nitric oxide. In turn, in heterozygous tight-skin mice 1, the resulting elevated nitric oxide levels may contribute to nitric oxide-mediated free radical endothelial cytotoxicity, although endothelium impairment may be related to other factors, particularly: Fbn-1 gene mutation and transforming growth factor-beta.
Marie
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Department of Zoology and Animal Biology, University of Geneva, Sciences III, 30 Quai Ernest Ansermet, 1211 Geneva 4, Switzerland. Isabelle.marie@chu-rouen.fr
Bény
J L
JL
D000109:Acetylcholine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000503:physiopathology; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D016285:Iloprost / Q000494:pharmacology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D012867:Skin / Q000473:pathology; D013373:Substance P / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D014665:Vasodilator Agents; D009569:Nitric Oxide; D013373:Substance P; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; D016285:Iloprost; D000109:Acetylcholine; D001920:Bradykinin; D002118:Calcium