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Epidermal growth factor receptor transactivation mediates the tonic and fibrogenic effects of endothelin in the aortic wall of transgenic mice
Author(s) -
Flamant Martin,
Tharaux PierreLouis,
Placier Sandrine,
Henrion Daniel,
Coffman Tom,
Chatziantoniou Christos,
Dussaule JeanClaude
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0115fje
Subject(s) - endocrinology , medicine , mapk/erk pathway , epidermal growth factor , endothelin receptor , transactivation , endothelin 1 , contractility , biology , receptor , chemistry , phosphorylation , microbiology and biotechnology , gene expression , biochemistry , gene
Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms in response to a chronic blood pressure increase. Vasoactive peptides, such as endothelin, participate in hypertension‐associated vascular fibrosis by stimulating collagen I formation and increasing contractility of arterial wall. In the present study, we tested the hypothesis that activation of the epidermal growth factor (EGF) receptor pathway mediates these events. Experiments were performed in transgenic mice harboring the luciferase gene under the control of the collagen I‐α2 chain promoter. Endothelin induced a rapid phosphorylation of the mitogen‐activated protein kinase (MAPK)/ERK and increased collagen I gene activity in freshly isolated aortas. This effect of endothelin was totally inhibited by an endothelin receptor antagonist, an EGF receptor phosphorylation inhibitor, and a blocker of the MAPK/ERK cascade. In parallel experiments, inhibition of EGF receptor phosphorylation decreased the endothelin‐induced pressor effect in isolated aortic rings and in anesthetized animals in vivo. In addition, the endothelin‐induced increase of blood pressure was blunted in the waved‐2 mice, a strain expressing functionally impaired EGF receptors. Our results provide the first evidence that the EGF receptor mediates at least two of the major actions of endothelin in the vascular tissue: contractility and fibrogenesis.