title: Botulinum Toxin A Upregulates Rac1, Cdc42, and RhoA Gene Expression in a Dose-Dependent Manner: In Vivo and in Vitro Study.
abstract: Angiogenesis is the development of new capillaries from existing blood vessels and is a prerequisite for the wound-healing process. Many lines of scientific evidences have shown that complicated roles of small guanosine triphosphatases (GTPases) (ras-related C3 botulinum toxin substrate 1 [Rac1], cell division control protein 42 [Cdc42], and ras homolog gene family, member A [RhoA]) in regulation of signal transduction pathways exist to transmit distinct cellular effects on the modulation of actin cytoskeleton remodeling such as cell cycle progression, cell survival, and cell motility. In addition, these small GTPases activate mitogen-activated protein kinase kinase kinases (MAP3Ks) leading to activated mitogen-activated protein kinase kinases (MAPKK), mitogen-activated protein kinase (MAPK), and various transcription factors such as vascular endothelial growth factor with involvement of MAPK signaling pathways.In this study, the authors hypothesized that botulinum toxin A increases angiogenesis via the expression of small GTPases in vivo and in vitro studies.In vivo experiment, 24 Sprague-Dawley rats were randomly divided into 2 groups: a control group and a botulinum toxin A group. Five days prior to superiorly based transverse rectus abdominis myocutaneous flap elevation, the botulinum toxin A (BoTA) group was pretreated with BoTA, while the control group was pretreated with normal saline. quantitative real-time polymerase chain reaction was performed to evaluate the expression of Rac1, RhoA, and Cdc42.The angiogenic effects of botulinum toxin A on human dermal fibroblasts were measured in vitro experiment. To understand the mechanism of botulinum toxin A on small GTPases production of fibroblasts, Rac1, Cdc42, and RhoA were measured using qRT-PCR.The relative messenger ribonucleic acid expression of Rac1, RhoA, and Cdc42 was significantly higher in the BoTA group than in the control group, in every zone and pedicle muscle, on postoperative days 1, 3, and 5. Levels of these molecules increased significantly in human dermal fibroblasts grown in the presence of BoTA compared with control group over 5 IU.Our in vivo and in vitro studies suggest that administration of BoTA upregulates the expression of RhoA, Rac1, and Cdc42 in a dose-dependent manner. MAPK signaling pathway might be involved in BoTA-induced angiogenesis mechanism.
  
  
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authors.affiliation: *Department of Plastic and Reconstructive Surgery, Yonsei University College of Medicine †Department of Plastic and Reconstructive Surgery, Kangbuk Samsung Hospital, College of Medicine, Sungkyunkwan University, Seoul, Korea.
authors.forename: Tae Hwan
authors.initials: TH
authors.lastname: Park
authors.forename: Ji Hae
authors.initials: JH
authors.lastname: Park
authors.forename: Choong Hyun
authors.initials: CH
authors.lastname: Chang
authors.forename: Dong Kyun
authors.initials: DK
authors.lastname: Rah
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D000818:Animals; D019274:Botulinum Toxins, Type A / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D064827:Myocutaneous Flap / Q000098:blood supply / Q000601:surgery; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017568:Rectus Abdominis / Q000098:blood supply / Q000601:surgery; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D020764:cdc42 GTP-Binding Protein / Q000187:drug effects*; D020830:rac1 GTP-Binding Protein / Q000187:drug effects*; D020742:rhoA GTP-Binding Protein / Q000187:drug effects*
chemical_list: D043925:Angiogenesis Inducing Agents; D019274:Botulinum Toxins, Type A; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein