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Endothelial dysfunction in murine model of systemic sclerosis: tight-skin mice 1
1Department of Zoology and Animal Biology, University of Geneva, Sciences III, 30 Quai Ernest Ansermet, 1211 Geneva 4, Switzerland. Isabelle.marie@chu-rouen.fr
The Journal of Investigative Dermatology
|December 18, 2002
Summary
Systemic sclerosis in mice impairs endothelial cell function and aortic relaxation, potentially due to altered receptor distribution and increased nitric oxide production leading to cytotoxicity.
Area of Science:
- Cardiovascular Biology
- Endothelial Cell Function
- Systemic Sclerosis Research
Background:
- Systemic sclerosis (SSc) is a complex autoimmune disease characterized by fibrosis and vascular abnormalities.
- Endothelial dysfunction is a hallmark of SSc, contributing to its pathogenesis.
- Understanding endothelial cell behavior in SSc models is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate endothelial cell function and nitric oxide's role in aortic relaxation in a murine model of systemic sclerosis (heterozygous tight-skin mice 1).
- To assess endothelial cell distribution, activation, and responses to vasodilators and Iloprost.
- To determine the impact of nitric oxide synthase inhibition on aortic relaxation.
Main Methods:
- Laser line confocal microscopy with Ca2+ fluorescent dyes to assess endothelial cell distribution and activation.
- Isometric tension measurement to evaluate endothelium-dependent relaxation and Iloprost-induced relaxation.
- Pharmacological inhibition of nitric oxide synthase to investigate nitric oxide's role.
Main Results:
- Heterozygous tight-skin mice 1 showed significantly fewer activated endothelial cells in response to adenosine triphosphate and Iloprost compared to controls.
- Maximal Ca2+ fluorescence intensity was reduced in response to adenosine triphosphate, bradykinin, and Iloprost in the SSc model.
- Aortic relaxation mediated by adenosine triphosphate and Iloprost was impaired in heterozygous tight-skin mice 1.
- Nitric oxide synthase inhibition markedly decreased relaxation to acetylcholine and adenosine triphosphate in the SSc model.
Conclusions:
- Endothelial cell receptors for vasodilators and Iloprost may be heterogeneously distributed or expressed in the thoracic aorta of heterozygous tight-skin mice 1, leading to vasodilatation dysfunction.
- Endothelium-dependent relaxation in this model appears highly dependent on nitric oxide release, possibly involving increased nitric oxide production.
- Elevated nitric oxide levels may contribute to endothelial cytotoxicity, with Fbn-1 gene mutation and TGF-β implicated in the observed endothelial impairment.
