Endothelial Dysfunction in an Ovine Model of Collagen-Induced Arthritis

Abstract

Background: Rheumatoid arthritis (RA) induces systemic inflammation, producing a range of co-morbidities including cardiovascular disease. An early vascular change is endothelial dysfunction, characterized by reduced endothelium-dependent vasodilation. The aim of this study was to assess endothelial function in isolated coronary and digital arteries using an ovine model of collagen-induced RA. Methods: Sheep were culled following induction of arthritis, and their endothelial function was compared to that of normal sheep. Paired arterial segments were mounted in a wire myograph and dilated with endothelium-dependent vasodilators [bradykinin, serotonin, carbachol and adenosine diphosphate (ADP); linked to either Gi or Gq signalling pathways] and endothelium-independent dilators (adenosine and sodium nitroprusside) to construct cumulative concentration-response curves. Results: Coronary arteries from arthritic sheep exhibited a significantly greater EC₅₀ value for bradykinin-induced relaxation compared to non-arthritic controls (2.9 × 10^-8<smlcap>M</smlcap> for arthritic sheep vs. 8.6 × 10^-9<smlcap>M</smlcap> for controls). Digital arteries from arthritic sheep also exhibited a significantly greater EC₅₀ for relaxation to ADP and a significant decrease in the carbachol maximal response. Responses to sodium nitroprusside were unchanged in both coronary and digital arteries. Conclusion: Sheep with RA demonstrated attenuated arterial relaxation to endothelium-dependent vasodilators. This may provide a useful model of endothelial dysfunction in chronic inflammatory conditions. The dysfunction did not appear to be associated with one specific G-protein signalling pathway.

Endothelial Dysfunction in Chronic Inflammatory Diseases

“…A collagen-induced arthritis model was recently described in sheep. Sheep with inflammatory arthritis demonstrated marked impairment in endothelium-dependent vasodilation in the coronary and digital arteries, whereas endothelium-independent vasodilation was intact [85]. Taken together, there is convincing evidence that animal models of inflammatory arthritis exhibit generalized endothelial dysfunction that may provide insight into the mechanisms linking inflammatory diseases and endothelial dysfunction in humans.…”

Collagen-induced arthritis increases inducible nitric oxide synthase not only in aorta but also in the cardiac and renal microcirculation of mice

“…However, evidence of vascular impairment related to collagen-induced arthritis (CIA) -an experimental model that reproduces the inflammatory mechanisms of RA with greater accuracy than other experimental models used for this purpose [16,18,21,[23][24][25] -is scarce in the literature. CIA-related endothelial dysfunction was demonstrated in mice aorta [26] as well as in sheep coronaries and digital arteries [27]. Conversely, Reynolds et al [25] failed to show CIA-induced endothelial dysfunction in mice aorta at the moment of onset of the earliest signs of joint inflammation.…”

Effect of Mesenchymal Precursor Cells on the Systemic Inflammatory Response and Endothelial Dysfunction in an Ovine Model of Collagen-Induced Arthritis

“…Bovine type II collagen solutions were prepared as previously described [ 23 ]. Arthritis was induced using a 6 week protocol, as previously described [ 21 , 22 ]. Sheep initially received a subcutaneous injection of bovine type II collagen solution (5mg/mL) in Freund’s complete adjuvant.…”

“…Arterial segments were prepared as described previously [ 22 ]. Following euthanasia, tissues were collected and placed in ice-cold oxygenated modified Krebs-Henseleit solution (KHS, 118.0mM/L NaCl, 4.7mM/L KCl, 1.2 mM/L MgSO 4 , 1.2mM/L KH 2 PO 4 , 25.0 mM/L NaHCO 3 , 11.1mM/L D-glucose and 2.5mM/L CaCl 2 ).…”

“…Previous studies by our group have demonstrated that in an ovine model of collagen-induced arthritis (CIA) involving just the left hock joint, there is evidence of systemic inflammation that also produces endothelial dysfunction in both the coronary and peripheral vascular bed [ 21 , 22 ]. This model therefore provides an opportunity to study the earliest cardiovascular changes associated with mild systemic inflammation.…”