title: Fibroblast growth factor mediates hypoxia-induced endothelin-- a receptor expression in lung artery smooth muscle cells.
abstract: We have previously demonstrated that endothelin (ET)-1 and its subtype A receptor (ET-AR) expression are increased in lung under hypoxic conditions and that activation of ET-AR by ET-1 is a major mediator of hypoxia-induced pulmonary hypertension in the rat. The present study tested the hypothesis that the hypoxia-responsive tyrosine kinase receptor-activating growth factors fibroblast growth factor (FGF)-1, FGF-2, and platelet-derived growth factor (PDGF)-BB stimulate expression of the ET-AR in pulmonary arterial smooth muscle cells (PASMCs). Quiescent rat PASMCs were incubated under hypoxia (1% O2), or with FGF-1, FGF-2, PDGF-BB, vascular endothelial growth factor, ET-1, angiotensin II, or atrial natriuretic peptide under normoxic conditions for 24 h. FGF-1 and -2 and PDGF-BB, but not hypoxia, vascular endothelial growth factor, ET-1, angiotensin II, or atrial natriuretic peptide, significantly increased ET-AR mRNA levels. FGF-1-induced ET-AR expression was inhibited by FGF-receptor inhibitor PD-166866, MEK inhibitor U-0126, transcription inhibitor actinomycin D, and translation inhibitor cycloheximide. In contrast, the stimulatory effect of FGF-1 on ET-AR mRNA expression was not altered by PI3 kinase, PKA, PKC, or adenylate cyclase inhibitors. PASMC ET-AR gene transcription, assessed by nuclear-runoff analysis, was increased by FGF-1. These results provide novel finding that ET-AR in PASMCs in vitro is unresponsive to hypoxia per se but is robustly simulated by tyrosine kinase receptor-associated growth factors (FGF-1, FGF-2, PDGF-BB) that themselves are stimulated by hypoxia in lung. This observation suggests a novel signaling mechanism that may be responsible for overexpression of ET-AR in lung, and may contribute to the hypoxia-induced pulmonary vasoconstriction, hypertension, and vascular remodeling in hypoxia-adapted animal.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham at Alabama, Birmingham, AL 35294, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Suzanne
authors.initials: S
authors.lastname: Oparil
authors.forename: Ju-Zhong
authors.initials: JZ
authors.lastname: Sun
authors.forename: John A
authors.initials: JA
authors.lastname: Thompson
authors.forename: Yiu-Fai
authors.initials: YF
authors.lastname: Chen
mesh_terms: D000818:Animals; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016220:Fibroblast Growth Factor 1 / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D044022:Receptor, Endothelin A / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D006133:Growth Substances; D019384:Nucleic Acid Synthesis Inhibitors; D011500:Protein Synthesis Inhibitors; D044022:Receptor, Endothelin A; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D003609:Dactinomycin; D005346:Fibroblast Growth Factors; D003513:Cycloheximide