ENDOTHELIN, AN ENDOTHELIAL-DEPENDENT VASOCONSTRICTOR IN SCLERODERMA - ENHANCED PRODUCTION AND PROFIBROTIC ACTION

The vascular endothelium is an important functional unit in the regulation of the vascular and perivascular environment. Various chemical and physical stimuli mediate an endothelial-dependent vasoconstriction through the release of endothelial soluble factors, such as the recently recognized endothelium-derived vasoconstrictor peptide called endothelin. The presence of circulating endothelin and the effect of cold exposure on plasma endothelin levels were investigated in patients with scleroderma and in healthy control subjects. Radioimmunoassay demonstrated a mean +/- SD plasma level of 10.7 +/- 7.3 pg/ml in the patients (n = 19) and 3.7 +/- 2 in the control subjects (n = 16) (P < 0.005). These levels were also assessed in 5 control subjects and 5 scleroderma patients before and after 30 minutes of total body cooling (to 15-degrees-C). The endothelin level did not change significantly in either group; however, 2 scleroderma patients showed a significant increase after cooling. The effects of endothelin on fibroblast proliferation and collagen synthesis were evaluated in order to assess the impact of released endothelin on the interstitium. A significant mitogenic effect and a collagen synthesis-enhancing effect, which were dose-dependent, were seen. The strong, characteristically prolonged, vasoconstrictor activity coupled with the profibrotic effect demonstrated here make it likely that disturbances in the control of endothelin production can contribute to the pathogenesis of scleroderma.