Microvascular abnormalities in adjuvant-induced arthritis: relationship to macrovascular endothelial function and markers of endothelial activation.

Abstract

To determine the time course of microvascular abnormalities and the link with macrovascular endothelial function and circulating markers of endothelial activation in adjuvant-induced arthritis (AIA) in rats. Microvascular function/structure and mechanics were studied in third-order mesenteric arteries subjected to flow and/or pressure on day 4 (preclinical arthritis), day 11 (very early arthritis), day 33 (severe disease), and day 90 (when inflammation has resolved) after AIA induction. Macrovascular function was studied in aortic rings, and blood pressure, plasma levels of C-reactive protein (CRP), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) were measured at each time point. Mesenteric flow-mediated vasodilation was significantly reduced from very early arthritis to chronic disease, whereas increased microvascular arterial stiffness was evident only on day 33. Macrovascular endothelial dysfunction was observed only on day 33. Thus, on day 90, whereas rats with AIA recovered normal macrovascular endothelial function, microvascular endothelial function remained impaired. No correlation was found between micro- and macrovascular endothelial function throughout the course of arthritis (r = 0.180, P = 0.229). Furthermore, no correlation was found between CRP levels, ICAM-1 levels, and endothelial function whatever the vascular bed. AIA was not associated with change in blood pressure or VCAM levels. Our findings indicate that microvascular endothelial dysfunction occurs earlier than macrovascular endothelial dysfunction and microvascular arterial stiffness during arthritis, suggesting that microvascular endothelial function would be a valuable tool for the early assessment of cardiovascular risk in RA. Neither the ICAM-1 level nor the CRP level is a good marker of micro- or macrovascular endothelial dysfunction.