096 Endothelin-1 expression and effects on pulmonary artery smooth muscle cells in idiopathic pulmonary arterial hypertension (IPAH)

Abstract

Endothelin 1 (ET-1) has been implicated in the development of pulmonary arterial hypertension (PAH) and asso-ciated with pulmonary vascular remodeling. ET-1 synthesis is increased in lungs from patients with PAH and ET-1 receptor anta-gonists clinically improve patients with PAH. However, the mecha-nisms by which ET-1 affects the pulmonary vessels and the respective rôles of ET-A and ET-B receptors in PAH remain a mat-ter of debate. We investigate in lung spécimens, pulmonary artery smooth muscle cells (PA-SMCs) and endothelial cells (PA-ECs) from 8 PAH patients and 8 controls: (i) ET-1 pulmonary expression, (ii) ET-1 synthesis by both cultured PA-SMCs and PA-ECs, (iii) the effects of ET-1 on PA-SMCs growth and migration, (iiii) the respective rôle and distribution of ET-A and ET-B receptor subtypes. We found that ET-1 synthesis was more marked in lungs from patients with PAH. ET-1 content in the médium was 32-35 fold higher in PA-ECs than in PA-SMCs. In both cell types, ET-1 synthesis was higher in PAH as compared to controls. ET-1 synthesis by PA-SMCs was markedly increased when the cells was stimulated by serotonin. This effect was abolished by fluoxe-tine a serotonin transporter inhibitor. Receptor density in cultured PA-SMCs was 2.3 fold higher in PAH patients than in controls. ET-A receptors predominate over ET-B from both PAH and controls. ET-1 had a weak mitogenic and migratory effect on PA-SMCs. The growth effect was mediated by ET-A, the migratory effect was due to activation of both ET-A and ET-B receptors. Thèse effects was more pronounced in cells from PAH than in controls. ET-1, ET-A and ET-B receptors expression are ele-vated in lungs and pulmonary vascular cells from patients with PAH and participate to pulmonary vascular remodelling. Thèse results support the hypothesis that antagonizing endothelin receptors may reduce pulmonary vascular remodelling in PAH patients.