Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Structural and Vasomotor Dysfunction in the Thoracic and Pulmonary Vessels of the Tight-Skin 1 (Tsk-1/) Mouse: Role of Endogenous Nitric Oxide.

Dooley1,  Audrey, Derrett-Smith1,  Emma C., Shiwen1,  Xu, Orie2,  Nelson N., Khan1,  Korsa, Denton4,  Christopher P., Clapp2,  Lucie

Center for Rheumatology and Connective Tissue Diseases, UCL Medical School, London, United Kingdom
Centre for Pharmacology, UCL Medical School, Rayne Institute, London, United Kingdom
Institute of Structural and Molecular Biology, UCL Medical School, London, United Kingdom
Royal Free Hospital, London, United Kingdom
University College London, London, United Kingdom

Background:

Systemic sclerosis (SSc) is a disease that features excessive collagen overproduction, fibrosis, as well as large and small vessel dysfunction. Previously we have shown that nitric oxide (NO), an important physiological signalling molecule and vasodilator, has abnormal metabolism in the skin of SSc patients and in the scleroderma-like syndrome of the tight-skin 1 (Tsk-1/+) mouse, an experimental model predisposed to the development of a connective tissue disease (CTD). The present study investigates contractile function and also the role of NO, in the thoracic aorta and pulmonary artery of the Tsk-1/+ mouse.

Methods:

Thoracic aortae and pulmonary arteries from heterozygous TSK-1/+ mice (age: 4, 8, 12 months) were compared with pallid littermates as control. Histology was used to stain sections for collagen or elastin expression. Vessel wall structure was further assessed by EM microscopy, and soluble collagen quantified by Sircol assay. Vascular isometric tension measurements of contractile function were studied using an organ bath or small vessel myograph. Potassium chloride (KCL; 30 mM and 80 mM) or phenylephrine (PE; 1 nM–50 mM) agonists were used to induce vasoconstriction in endothelium-dependant or independent vascular rings. Vascular rings were also pre-incubated with L-NAME (100 mM), a non-specific NO synthase (NOS) inhibitor, or 1400W (5 mM), a specific inducible NOS inhibitor. The NO donor sodium nitroprusside (SNP; 1 nM–50 mM) was used to assess endothelial-independent relaxation.

Results:

In Tsk-1/+ thoracic aorta, using histological staining and EM microscopy we observed thickening of the aortic arch wall, disruption of the elastic fiber architecture, and elevated levels of collagen in the aortic adventitia. Aortic soluble collagen content was greater in the Tsk-1/+ group compared to controls. Isometric tension measurement revealed that both KCL and PE-induced contractions were reduced in aortic Tsk-1/+ vessels at all ages studied. PE-induced maximal responses (Emax) at 4 months were (Tsk-1/+ 217.2 ± 6.3 mg; control 411.0 ± 10.1 mg), at 8 months (Tsk-1/+ 322.5 ± 32.4 mg; control 618.1 ± 17.9 mg), and at 12 months (Tsk-1/+ 319.4 ± 44.7 mg; control 576.2 ± 31.0 mg). Similarly, at 4 months in pulmonary Tsk-1/+ vessels, PE-induced maximal responses were reduced. Inhibition of endogenous NO production in aortic control vessels, by either pre-treatment with L-NAME or removal of the endothelium, increased PE-induced contractions by 61% but had no significant effect in the aortic Tsk-1/+ group, indicating reduced basal NO bioavailability. Pre-treatment with 1400W had no significant effect on either group. SNP-induced endothelium-independent relaxations, completely dilated PE-induced contraction of both control and Tsk-1/+ aortas, indicating no difference in smooth muscle sensitivity to NO.

Conclusion:

The pathogenesis of the Tsk-1/+ mouse model of CTD exhibits vasomotor dysfunction of the thoracic aorta that could be associated with increased collagen deposition and reduced NO bioavailability.

To cite this abstract, please use the following information:
Dooley, Audrey, Derrett-Smith, Emma C., Shiwen, Xu, Orie, Nelson N., Khan, Korsa, Denton, Christopher P., et al; Structural and Vasomotor Dysfunction in the Thoracic and Pulmonary Vessels of the Tight-Skin 1 (Tsk-1/) Mouse: Role of Endogenous Nitric Oxide. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2005
DOI: 10.1002/art.29770

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