Prostanoid receptor subtypes involved in treprostinil-mediated vasodilation of rat pulmonary arteries and in treprostinil-mediated inhibition of collagen gene expression of human lung fibroblasts

•Determination of the prostanoid receptors in contraction of pulmonary vascular smooth muscle and expression of collagen genes.•In rat pulmonary arteries, the IP receptor is the dominant receptor mediating TRE-induced vasodilation.•The DP1 receptor is involved at high TRE concentration and the EP3 receptor modulated this response in pulmonary arteries with intact endothelium.•In human lung fibroblasts, the EP2 receptor is the subtype involved in gene expression of collagen synthesis and contractility in response to TRE. Treprostinil (TRE) is a potent pulmonary vasodilator with effects on other pathological aspects of pulmonary arterial hypertension. In this study, the prostanoid receptors involved in TRE-induced relaxation of isolated rat pulmonary arteries and TRE-induced inhibition of increased gene expression in collagen synthesis and contractility of human lung fibroblasts were determined. TRE (0.01−100 μM) relaxed prostaglandin F2α-precontracted rat pulmonary arteries which was attenuated by denudation of the vascular endothelium. TRE-induced relaxation was predominantly blocked by the IP receptor antagonist RO3244194 (1 μM), with slightly greater inhibition in endothelium-denuded tissue. At higher TRE concentrations (> 1 μM), the DP1 receptor antagonist BW A868C (1 μM) also inhibited relaxation reaching significance above 10 μM. In contrast, the EP3 receptor antagonist L798106 (1 μM) accentuated TRE-induced relaxation of pulmonary arteries with intact endothelium. In human lung fibroblasts, the EP2 receptor antagonist PF-04418948 (1 μM) blocked transforming growth factor β1 (TGF-β1)-increased expression of collagen synthesis (COL1A1 and COL1A2) and fibroblast contractility (ACTG2) genes in presence of TRE (0.1 μM). In conclusion, the IP receptor located on rat pulmonary vascular smooth muscle and endothelium is the primary receptor mediating vasorelaxation, while the DP1 receptor present on the rat endothelium is involved only at higher TRE concentrations. In human lung fibroblasts, the EP2 receptor is the dominant receptor subtype involved in suppression of increased collagen synthesis and fibroblast contractility gene expression induced by TGF-β1 in the presence of TRE.