title: Endothelial cell-derived endothelin-1 is involved in abnormal scar formation by dermal fibroblasts through RhoA/Rho-kinase pathway.
abstract: Hypertrophic scars and keloids are characterized by excessive dermal deposition of extracellular matrix due to fibroblast-to-myofibroblast differentiation. Endothelin-1 (ET-1) is primarily produced by vascular endothelial cells and plays multiple roles in the wound-healing response and organ fibrogenesis. In this study, we investigated the pathophysiological significance of ET-1 and involvement of RhoA, a member of the Rho GTPases, in hypertrophic scar/keloid formation. We found that ET-1 expression on dermal microvascular endothelial cells (ECs) in hypertrophic scars and keloids was higher than that in normal skin and mature scars. We also confirmed that ET-1 induced myofibroblast differentiation and collagen synthesis in cultured human dermal fibroblasts through the RhoA/Rho-kinase pathway. Finally, since hypertrophic scar/keloid formation was most prominent in areas exposed to mechanical stretch, we examined how mechanical stretch affected ET-1 secretion in human dermal microvascular ECs, and found that mechanical stretch increased ET-1 gene expression and secretion from ECs. Taken together, these results suggest that dermal microvascular ECs release ET-1 in response to mechanical stretch, and thereby contribute to the formation of hypertrophic scars and keloids through the RhoA/Rho-kinase pathway.
authors.affiliation: Department of Plastic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kiya
authors.affiliation: Department of Plastic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Tateki
authors.initials: T
authors.lastname: Kubo
authors.affiliation: Department of Plastic Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Kawai
authors.affiliation: Department of Pharmacology, Wakayama Medical University, Kimiidera, Wakayama, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Matsuzaki
authors.affiliation: Department of Plastic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Maeda
authors.affiliation: Department of Plastic Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Department of Plastic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Nishibayashi
authors.affiliation: Department of Plastic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kanazawa
authors.affiliation: Department of Plastic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yano
authors.affiliation: Department of Child Development and Molecular Brain Science, United Graduate School of Child Development, Osaka University, Suita, Osaka, Japan.
authors.forename: Genki
authors.initials: G
authors.lastname: Amano
authors.affiliation: Department of Child Development and Molecular Brain Science, United Graduate School of Child Development, Osaka University, Suita, Osaka, Japan.
authors.forename: Taiichi
authors.initials: T
authors.lastname: Katayama
authors.affiliation: Department of Plastic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Ko
authors.initials: K
authors.lastname: Hosokawa
mesh_terms: D002454:Cell Differentiation; D017439:Cicatrix, Hypertrophic / Q000209:etiology* / Q000378:metabolism; D024042:Collagen Type I / Q000096:biosynthesis; D042783:Endothelial Cells / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism*; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D007627:Keloid / Q000209:etiology* / Q000378:metabolism; D061251:Primary Cell Culture; D012867:Skin / Q000098:blood supply; D013314:Stress, Mechanical; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D019332:Endothelin-1; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein
keywords: hypertrophic scar; keloid; mechanical stretch; myofibroblasts; α-smooth muscle actin