title: Endothelin-1 induces pulmonary but not aortic smooth muscle cell migration by activating ERK1/2 MAP kinase.
abstract: Endothelin 1 (ET-1) is an endogenous peptide that promotes vasoconstriction, endothelial and smooth muscle cell (SMC) proliferation, and fibrosis. ET-1 receptor antagonists are an important treatment strategy for pulmonary arterial hypertension, but less effective in systemic vascular disease. This observation suggests a special role for ET-1 in the pulmonary circulation. We hypothesized that ET-1 contributes to the pathogenesis of pulmonary arterial hypertension, in part, by promoting pulmonary vascular SMC migration. ET-1 treatment promoted migration in 3 distinct types of cultured pulmonary SMC. Pulmonary SMC migration was blocked by an ETA receptor selective agonist and a combined ETA-ETB antagonist, but not by a selective ETB antagonist. In contrast to the effect on pulmonary SMCs, ET-1 had no effect on migration of aortic SMCs. Flow cytometry showed that the ETA receptor was expressed at comparable levels on pulmonary and aortic SMCs, excluding receptor density as an explanation for the divergent effect. ET-1-induced pulmonary SMC migration was blocked by the structurally distinct MEK inhibitors PD98059 and U0126, consistent with a role for ERK1/2 MAP kinase. By Western blot in cultured cells and immunohistochemistry in ex vivo vessels, ET-1 stimulated phosphorylation of ERK1/2 as efficaciously as platelet-derived growth factor in pulmonary, but not aortic, SMCs. In conclusion, ET-1 induces SMC migration, with the ETA receptor tightly coupled to ERK1/2 phosphorylation only in the pulmonary circulation. This finding may help explain the striking difference in the efficacy of endothelin receptor blockers for pulmonary hypertension as compared to that for systemic cardiovascular disease.
authors: Aab Cardiovascular Research Institute and Department of Pulmonary and Critical Care Medicine, University of Rochester, 400 Red Creek Drive, Suite 110, Rochester, NY 14623, USA.
authors: David F
authors: DF
authors: Meoli
authors: R James
authors: RJ
authors: White
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D000077214:Becaplermin; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D006801:Humans; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D011651:Pulmonary Artery / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D017540:Tunica Media / Q000187:drug effects / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D044022:Receptor, Endothelin A; C076213:PD 142893; D000077214:Becaplermin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C072247:cyclo(Trp-Asp-Pro-Val-Leu)