title: Copper-induced vascular endothelial growth factor expression and wound healing.
abstract: Angiogenesis plays a central role in wound healing. Among many known growth factors, vascular endothelial growth factor (VEGF) is believed to be the most prevalent, efficacious, and long-term signal that is known to stimulate angiogenesis in wounds. Whereas a direct role of copper to facilitate angiogenesis has been evident two decades ago, the specific targets of copper action remained unclear. This report presents first evidence showing that inducible VEGF expression is sensitive to copper and that the angiogenic potential of copper may be harnessed to accelerate dermal wound contraction and closure. At physiologically relevant concentrations, copper sulfate induced VEGF expression in primary as well as transformed human keratinocytes. Copper shared some of the pathways utilized by hypoxia to regulate VEGF expression. Topical copper sulfate accelerated closure of excisional murine dermal wound allowed to heal by secondary intention. Copper-sensitive pathways regulate key mediators of wound healing such as angiogenesis and extracellular matrix remodeling. Copper-based therapeutics represents a feasible approach to promote dermal wound healing.
authors.affiliation: Laboratory of Molecular Medicine, Department of Surgery, 512 Davis Heart & Lung Research Institute, The Ohio State University Medical Center, Columbus, Ohio 43210, USA. sen-1@medctr.osu.edu
authors.forename: Chandan K
authors.initials: CK
authors.lastname: Sen
authors.forename: Savita
authors.initials: S
authors.lastname: Khanna
authors.forename: Mika
authors.initials: M
authors.lastname: Venojarvi
authors.forename: Prashant
authors.initials: P
authors.lastname: Trikha
authors.forename: E Christopher
authors.initials: EC
authors.lastname: Ellison
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Hunt
authors.forename: Sashwati
authors.initials: S
authors.lastname: Roy
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D003300:Copper / Q000494:pharmacology* / Q000627:therapeutic use; D019327:Copper Sulfate / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000032:analysis / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D062385:Hydroxybenzoates / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000494:pharmacology; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008222:Lymphokines / Q000032:analysis / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014945:Wound Healing; D014947:Wounds and Injuries / Q000378:metabolism / Q000473:pathology
chemical_list: D016228:Endothelial Growth Factors; D062385:Hydroxybenzoates; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D017665:Hydroxyl Radical; C009091:protocatechuic acid; D003300:Copper; D006861:Hydrogen Peroxide; D019327:Copper Sulfate