Endothelial Dysfunction in Murine Model of Systemic Sclerosis: Tight-skin Mice 1

• Published in: Journal of investigative dermatology Vol. 119; no. 6; pp. 1379 - 1387
• Main Authors: Marie, I., Bény, J.L.
• Format: Journal Article
• Language: English
• Published: Danvers, MA Elsevier Inc 01.12.2002; Nature Publishing; Elsevier Limited
• Subjects: Acetylcholine - pharmacology; Adenosine Triphosphate - pharmacology; Animals; Aorta, Thoracic - physiopathology; Biological and medical sciences; Bradykinin - pharmacology; Calcium - metabolism; Disease Models, Animal; Endothelium, Vascular - metabolism; Endothelium, Vascular - physiopathology; endothelium-dependent relaxation; Iloprost - pharmacology; In Vitro Techniques; Isometric Contraction - drug effects; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microscopy, Confocal; nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase - antagonists & inhibitors; prostacyclin analog; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Scleroderma, Systemic - genetics; Scleroderma, Systemic - metabolism; Scleroderma, Systemic - physiopathology; Skin - pathology; Substance P - pharmacology; systemic sclerosis; tight-skin mice; Vasodilation - drug effects; Vasodilation - physiology; Vasodilator Agents - pharmacology; prostacyclin analog; nitric oxide; systemic sclerosis; endothelium-dependent relaxation; tight-skin mice; Immunopathology; Connective tissue disease; Skin disease; Endothelial cell; Rodentia; Autoimmune disease; Vertebrata; Mammalia; Mouse; Animal; Nitric oxide; Systemic disease; Aorta; Models; Endothelium derived relaxing factor; endothelium- dependent relaxation/nitric oxide/prostacyclin analog/systemic sclerosis/tight-skin mice; Scleroderma
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1046/j.1523-1747.2002.19614.x

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-β.