title: Signaling mechanism underlying the promotion of keratinocyte migration by angiotensin II.
abstract: Re-epithelialization begins early during skin wound healing and is regulated by various growth factors and cytokines. Angiotensin II promotes the migration of keratinocytes and thereby contributes to wound healing. We investigated the mechanism by which angiotensin II stimulates human keratinocyte migration. Angiotensin II-induced keratinocyte migration was inhibited by an angiotensin II type 1 receptor (AT1R) antagonist (candesartan) or an angiotensin II type 2 receptor (AT2R) antagonist (PD123319) as well as by depletion of AT1R or AT2R. A biased agonist for AT1R, [Sar(1),Ile(4),Ile(8)]angiotensin II, induced cell migration, whereas depletion of β-arrestin2 inhibited angiotensin II-induced migration. Angiotensin II-induced migration was blocked by neutralizing antibodies to transforming growth factor-β (TGF-β) as well as by the TGF-β receptor inhibitor SB431542. The amount of TGF-β1 was increased in the culture medium of angiotensin II-treated cells, and this effect was inhibited by candesartan or PD123319. Both angiotensin II- and TGF-β-induced cell migration were inhibited by neutralizing antibodies to the epidermal growth factor (EGF) receptor but not by those to EGF receptor ligands. Angiotensin II-induced phosphorylation of the EGF receptor, and this effect was inhibited by candesartan, PD123319, SB431542, or depletion of β-arrestin2, but not by neutralizing antibodies to heparin-binding EGF-like growth factor. Our results indicate that β-arrestin-dependent signaling downstream of AT1R as well as AT2R signaling are necessary for angiotensin II-induced keratinocyte migration, and that such signaling promotes generation of the active form of TGF-β, consequent activation of the TGF-β receptor, and transactivation of the EGF receptor by the TGF-β receptor.
authors.affiliation: Department of Pharmacology (H.S., K.M., Y.T., T.H., M.I.) and Department of Ophthalmology (T.N.), Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sakai
authors.affiliation: Department of Pharmacology (H.S., K.M., Y.T., T.H., M.I.) and Department of Ophthalmology (T.N.), Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsuura
authors.affiliation: Department of Pharmacology (H.S., K.M., Y.T., T.H., M.I.) and Department of Ophthalmology (T.N.), Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Pharmacology (H.S., K.M., Y.T., T.H., M.I.) and Department of Ophthalmology (T.N.), Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Honda
authors.affiliation: Department of Pharmacology (H.S., K.M., Y.T., T.H., M.I.) and Department of Ophthalmology (T.N.), Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Teruo
authors.initials: T
authors.lastname: Nishida
authors.affiliation: Department of Pharmacology (H.S., K.M., Y.T., T.H., M.I.) and Department of Ophthalmology (T.N.), Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan minui@yamaguchi-u.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Inui
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000502:physiology*; D008297:Male; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D000804:Angiotensin II