A novel function of angiotensin II in skin wound healing. Induction of fibroblast and keratinocyte migration by angiotensin II via heparin-binding epidermal growth factor (EGF)-like growth factor-mediated EGF receptor transactivation.
The role of angiotensin II (Ang II) in the control of systemic blood pressure and volume homeostasis is well known and has been extensively studied. Recently, Ang II was suggested to also have a function in skin wound healing. In the present study, the in vivo function of Ang II in skin wound healing was investigated using Ang II type 1 receptor (AT1R) knock-out mice. Wound healing in these mice was found to be markedly delayed. Keratinocytes and fibroblasts play important roles in wound healing, and thus the effect of Ang II on the migration of these cells was examined. Ang II stimulated keratinocyte and fibroblast migration in a dose-dependent manner. It has been reported that G protein-coupled receptor (GPCR) activation induces epidermal growth factor (EGF) receptor (EGFR) transactivation through the shedding of heparin-binding EGF-like growth factor (HB-EGF). As AT1R is a GPCR, it was hypothesized that Ang II-induced keratinocyte and fibroblast migration is mediated by EGFR transactivation. Ang II induced EGFR phosphorylation, which was inhibited by an AT1R antagonist, HB-EGF neutralizing antibody, and an HB-EGF antagonist in both keratinocytes and in fibroblasts. Moreover, Ang II-induced migration of keratinocytes and fibroblasts was also prevented by these inhibitors. Taken together, these findings clearly demonstrate, for the first time, that Ang II plays an important role in skin wound healing and that it functions by accelerating keratinocyte and fibroblast migration in a process mediated by HB-EGF shedding.
Yahata
Yoko
Y
Department of Dermatology, Ehime University School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.
Shirakata
Yuji
Y
Department of Dermatology, Ehime University School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan. Electronic address: shirakat@m.ehime-u.ac.jp.
Tokumaru
Sho
S
Department of Dermatology, Ehime University School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.
Yang
Lujun
L
Department of Dermatology, Ehime University School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.
Dai
Xiuju
X
Department of Dermatology, Ehime University School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.
Tohyama
Mikiko
M
Department of Dermatology, Ehime University School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.
Tsuda
Teruko
T
Department of Dermatology, Ehime University School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.
Sayama
Koji
K
Department of Dermatology, Ehime University School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.
Iwai
Masaru
M
Division of Medical Biochemistry and Cardiovascular Biology, Ehime University School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.
Horiuchi
Masatsugu
M
Division of Medical Biochemistry and Cardiovascular Biology, Ehime University School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.
Hashimoto
Koji
K
Department of Dermatology, Ehime University School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.
D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D000078404:Epidermal Cells; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D012867:Skin / Q000293:injuries / Q000378:metabolism*; D015533:Transcriptional Activation; D014945:Wound Healing / Q000502:physiology*
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D004815:Epidermal Growth Factor; D066246:ErbB Receptors