Localization of endothelin-1 and its binding sites in scleroderma skin

Abstract

Objective: Endothelin-1 (ET-1) has been implicated in the pathogenesis of systemic sclerosis (SSc) as it is both a potent vasoconstrictor and fibroblast mitogen and is raised in the circulation of patients with SSc and primary Raynaud's phenomenon.

Methods: We examined the localization and level of expression of ET-1 and its putative receptors in clinically "uninvolved" (i.e., prescleroderma skin) and involved skin from patients with diffuse cutaneous systemic sclerosis (dcSSc), using the alkaline phosphatase antialkaline phosphatase technique while ET-1 binding sites were examined using in vitro autoradiography.

Results: There was an increase in dermal ET-1 staining in clinically uninvolved and involved skin from patients with early active dcSSc compared with late stage fibrotic SSc skin and normal skin from healthy volunteers. Increased ET-1 staining was associated predominantly with the superficial vessels in the SSc skin sections. In addition, there was a significant increase in [125I]ET-1 binding to superficial vessels and the dermal/epidermal junction in SSc skin compared with the binding to similar structures in normal tissue. There was no change in [125I]ET-1 binding to the deep dermal vessels in both SSc and normal skin. This increase in [125I]ET-1 binding in SSc skin was not maintained with increasing tissue fibrosis.

Conclusion: The presence of increased ET-1 levels as well as its binding sites in both the prescleroderma and involved skin of patients with dcSSc compared to controls suggests that ET-1 may play a role in the pathology of dermal fibrosis and vasoconstriction in SSc.