The role of endothelin in connective tissue diseases.

Vascular dysregulation is centrally involved in the pathogenesis of diverse rheumatological diseases. The resulting pulmonary arterial hypertension as well as Raynaud's phenomenon may be accompanied by distinct tissue fibrosis. The pleiotropic cytokine endothelin may represent a link between these vascular and fibrotic processes, which are most evidently seen in systemic sclerosis. Among three closely related isoforms, endothelin-1 (ET-1) is the most common in humans, and is often referred to as ET in the literature. ET-1 is involved in physiological processes of vascular tone and mitogenesis, whereas under pathological conditions fibrosis, vascular hypertension and inflammation are induced. Its expression is dependent on tissue and cell type as well as on the underlying disease entity and its stage. Elevated plasma and tissue levels have been demonstrated in idiopathic pulmonary hypertension, systemic sclerosis as well as in other connective tissue diseases and correlate to haemodynamic parameters and disease outcome. The biological effects are mediated by two membrane receptors (ET-1-receptor A and B) belonging to the G-protein-coupled serpentine family. Both receptors are differentially expressed by different cell types as well as in different diseases entities. Antagonizing these receptors therapeutically has already been successful. However, the differential action of ET is counterbalanced by other mediators, prominently nitric oxide. Consequently, the suspected direct relation of vascular and fibrotic processes through ET still needs to be further evaluated.