Mechanisms of endothelial dysfunction in rheumatoid arthritis: lessons from animal studies

Abstract

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by articular and extra-articular manifestations involving cardiovascular diseases (CVDs), which account for 30% to 50% of all deaths. In patients with RA, atherosclerosis lesions occur earlier and have a more rapid evolution than in the general population. Beyond mortality, the impact of CVD on quality of life, combined with the associated increase in health-care costs, renders CVD in RA a major public health problem. Recent studies showed that patients with RA are characterized by the presence of endothelial dysfunction (ED), which is recognized as a key event in the development of atherosclerosis. By definition, ED is a functional and reversible alteration of endothelial cells, leading to a shift of the actions of the endothelium toward reduced vasodilation, proinflammatory state and proliferative and prothrombotic properties. Although the improvement of endothelial function is becoming an important element of the global management of patients with RA, the mechanistic determinants of ED in RA are still poorly understood. Animal models of RA provide the unique opportunity to unravel the pathophysiological features of ED in RA. The present review summarizes the available data on mechanisms underlying ED in animal models of RA and proposes attractive prospects in order to discover novel therapeutic strategies of RA-associated ED.

Microvascular Abnormalities in Adjuvant‐Induced Arthritis: Relationship to Macrovascular Endothelial Function and Markers of Endothelial Activation

“…In conduit arteries, our results demonstrated that endothelial dysfunction was absent at the preclinical stage and during very early AIA but became evident at the time of acute clinical inflammation (day 33). These data are consistent with previous results obtained in animal models of RA and in RA patients .…”

New insights to the mechanisms underlying atherosclerosis in rheumatoid arthritis

“…ED leads to increase in permeability to inflammatory cells such as monocytes. On the other hand, this endothelial dysfunction is associated with increased expression of adhesion molecules and inflammatory cytokines, which facilitate penetration of monocytes to the sub‐endothelium . In a mouse model of RA it has been shown that acetylcholine‐induced endothelium vasorelaxation was decreased .…”

“…On the other hand, this endothelial dysfunction is associated with increased expression of adhesion molecules and inflammatory cytokines, which facilitate penetration of monocytes to the sub‐endothelium . In a mouse model of RA it has been shown that acetylcholine‐induced endothelium vasorelaxation was decreased . On the other hand, proper function of the endothelium depends on the equilibrium between vasoconstrictors such as angiotensin II (ANG‐II), thromboxane A2 (TXA2) and endothelin‐1 and vasodilator substances such as prostacyclin (PGI2), nitric oxide (NO) and endothelium‐derived hyperpolarizing factors (EDHFs) .…”

Glucocorticoids and endothelial function in inflammatory diseases: focus on rheumatoid arthritis

“…Data about endothelial mechanisms involved in ED have been provided by studies on animal models of RA. As reported in a recent review [23], RA-associated ED is secondary to decreased NO availability, decreased endothelial NOS expression/activity, uncoupling of endothelial NOS, increased arginase activity, excess of superoxide anion production, impaired EDHF production, increased synthesis of prostanoids and increased angiotensin II production.…”