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Assessment of vascular function in systemic sclerosis: indications of the development of nitrate tolerance as a result of enhanced endothelial nitric oxide production
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
Mälar Hospital, Eskilstuna, Sweden.
Sahlgrenska University Hospital, Gothenburg, Sweden.
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2002 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 46, no 5, 1324-1332 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To investigate the relationship between endothelium-dependent and endothelium-independent functions and the stiffness of conduit arteries as well as levels of endothelial activation markers in patients with systemic sclerosis (SSc).

METHODS: Endothelium-dependent (i.e., flow-mediated) and endothelium-independent (i.e., nitroglycerin-induced) dilation of the brachial artery was measured as the percentage of change from baseline (FMD% and NTG%, respectively) in 24 SSc patients and 24 age- and sex-matched healthy controls by high-resolution ultrasound imaging. The maximum increase in systolic pressure per unit of time (dP/dt(max)), as a measure of arterial wall stiffness, was assessed in the radial artery by pulse applanation tonometry. Plasma nitrate, the most important metabolite of nitric oxide, and 24-hour urinary excretion of nitrate were measured by gas chromatography mass spectrometry. Soluble E-selectin and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured by enzyme-linked immunosorbent assay.

RESULTS: Brachial artery FMD% and NTG% did not differ between SSc patients and controls. Radial artery dP/dt(max) was significantly increased in the patients and correlated significantly with elevated levels of plasma nitrate and sVCAM-1. Twenty-four-hour urinary nitrate excretion tended to be elevated. Brachial artery NTG% was significantly inversely correlated with levels of plasma nitrate and soluble endothelial adhesion molecules.

CONCLUSION: The ability of the brachial arteries to dilate in response to hyperemia and nitroglycerin challenge is preserved in SSc. Stiffness of the radial artery is increased, however. Endothelial activation seems to determine the extent of the brachial artery NTG% and the radial artery dP/dt(max). The data are compatible with the hypothesis that nitrate tolerance is present in the vascular smooth muscle cells of the brachial artery wall in SSc.

Place, publisher, year, edition, pages
2002. Vol. 46, no 5, 1324-1332 p.
National Category
Rheumatology and Autoimmunity
URN: urn:nbn:se:umu:diva-21511DOI: 10.1002/art.10191PubMedID: 12115240OAI: diva2:211358
Available from: 2009-04-14 Created: 2009-04-14 Last updated: 2011-01-21Bibliographically approved
In thesis
1. Systemic sclerosis: vascular, pulmonary and immunological aspects
Open this publication in new window or tab >>Systemic sclerosis: vascular, pulmonary and immunological aspects
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In systemic sclerosis (SSc), interstitial lung disease (ILD) and engagement of the vascular system lead to increased morbidity and mortality.

The aim of this thesis was to elucidate, in a consecutively included cohort of SSc (limited and diffuse) patients (n = 33), the T cell cytokine profile driving the disease in ILD and to explore the role of matrix metalloproteinase 9 (MMP-9) and its inhibitor: tissue inhibitor of metalloproteinase 1 (TIMP-1) in the extracellular matrix (ECM) degrading process leading to fibrous scarring and honey combing. Moreover, to characterize the role of nitric oxide (NO) in vascular engagement.

Peripheral arterial changes cause Raynaud’s phenomenon and digital ulcers. Nitric oxide (NO) a main inducer of vasodilation is produced by endothelial nitric oxide synthase (eNOS) in response to changes in blood flow or by inflammatory cytokine inducible (i) NOS. In the vascular smooth muscle cell (VSMC) NO activates guanylate cyclase to produce cGMP, causing relaxation. We showed elevated plasma nitrate, a degradation product of NO, and increased urinary excretion of nitrate and cGMP. Plasma nitrate correlated with elevated levels of endothelial adhesion molecules: endothelial (E) selectin and vascular adhesion molecule 1, indicating that the activated endothelium is the site of NO synthesis by iNOS. Endothelial staining for E-selectin and the finding of iNOS and eNOS in SSc skin biopsies supported this notion.

In SSc increased vascular stiffness may limit the NO vasodilatory effects. We found normal endothelium-dependent (i.e. flow mediated (FMD%)) and endothelium-independent (i.e. nitroglycerin-induced (NTG%)) vasodilation in the brachial artery. Radial arterial wall stiffness measured as maximum increase in pulse pressure (dP/dtmax) was increased. FMD% and especially NTG% correlated negatively and dP/dtmax positively to measures of endothelial inflammation: plasma- nitrate and adhesion molecule levels. Thus inflammatory vascular wall changes may interfere with dilation as may the presence of nitrate tolerance.

We found elevated alveolar MMP-9 in both its pro- and active form in ILD. The levels correlated to decline in lung capacity, pointing at a causal relation. We suggest that neutrophils secrete MMP-9, which may degrade collagen IV, (the main constituent of basal membranes), collagen V, gelatins, proteoglycans and elastin. MMP-9 activity is partly regulated by the binding of pro- and active form to TIMP-1. Alveolar TIMP-1, which even stimulates fibroblast ECM synthesis, was increased independent of ILD.

The inflammatory process in ILD is orchestrated by activated T helper (h) lymphocytes. We found a mixed Th1/Th2 reaction in SSc alveolar T cells expressing messenger for interferon gamma (Th1), IL-6 and IL-10 (both Th2). No particular cytokine mRNA profile distinguished alveolar T cells in ILD.

Neutrophils invaded the bronchial epithelium, which seemed otherwise inert as levels of inflammatory cytokine sensitive transcription factors and their nuclear translocation tended to be low. The neutrophil recruitment pathway is uncertain as chemoattractants and endothelial adhesion molecules were normally expressed.

In conclusion, MMP-9 probably causes degradation of lung tissue in ILD and may represent a future therapeutic target. Alveolar T cells show a mixed Th1/Th2 cytokine profile independent of ILD. Neutrophils invade the bronchial epithelium. Activated endothelium produces increased amounts of NO and adhesion molecules and the level of activation influences brachial arterial FMD% and NTG% and radial arterial compliance. Nitrate tolerance may be present.

Place, publisher, year, edition, pages
Umeå: Reumatologi, 2008. 67 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1205
Systemic sclerosis, interstitial lung disease, MMP-9, Th1/Th2, transcription factors, NO, iNOS, E-selectin, endothelium-dependent dilation, endothelium-independent dilation.
National Category
Rheumatology and Autoimmunity
urn:nbn:se:umu:diva-1806 (URN)978-91-7264-625-4 (ISBN)
Public defence
2008-09-26, Sal D, 9tr, Tandläkarhögskolan, NUS, Umeå, 12:00 (English)
Available from: 2008-09-03 Created: 2008-09-03 Last updated: 2010-01-18Bibliographically approved

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