RRC ID 4778
Author Ozawa K, Kondo T, Hori O, Kitao Y, Stern DM, Eisenmenger W, Ogawa S, Ohshima T.
Title Expression of the oxygen-regulated protein ORP150 accelerates wound healing by modulating intracellular VEGF transport.
Journal J Clin Invest
Abstract Expression of angiogenic factors such as VEGF under conditions of hypoxia or other kinds of cell stress contributes to neovascularization during wound healing. The inducible endoplasmic reticulum chaperone oxygen-regulated protein 150 (ORP150) is expressed in human wounds along with VEGF. Colocalization of these two molecules was observed in macrophages in the neovasculature, suggesting a role of ORP150 in the promotion of angiogenesis. Local administration of ORP150 sense adenovirus to wounds of diabetic mice, a treatment that efficiently targeted this gene product to the macrophages of wound beds, increased VEGF antigen in wounds and accelerated repair and neovascularization. In cultured human macrophages, inhibition of ORP150 expression caused retention of VEGF antigen within the endoplasmic reticulum (ER), while overexpression of ORP150 promoted the secretion of VEGF into hypoxic culture supernatants. Taken together, these data suggest an important role for ORP150 in the setting of impaired wound repair and identify a key, inducible chaperone-like molecule in the ER. This novel facet of the angiogenic response may be amenable to therapeutic manipulation.
Volume 108(1)
Pages 41-50
Published 2001-7-1
DOI 10.1172/JCI11772
PMID 11435456
PMC PMC209338
MeSH Adenoviridae / genetics Animals Cell Hypoxia / physiology* Cells, Cultured Culture Media, Conditioned DNA-Binding Proteins / physiology Diabetes Complications Diabetes Mellitus / genetics Endoplasmic Reticulum / metabolism Endothelial Growth Factors / biosynthesis Endothelial Growth Factors / genetics Endothelial Growth Factors / physiology* Endothelium, Vascular / cytology Endothelium, Vascular / metabolism Female Fibroblast Growth Factor 2 / physiology Gene Expression Regulation / drug effects Genetic Therapy Genetic Vectors / administration & dosage Genetic Vectors / genetics HSP70 Heat-Shock Proteins Humans Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Lymphokines / biosynthesis Lymphokines / genetics Lymphokines / physiology* Macrophages / metabolism Male Mice Mice, Inbred C57BL Mice, Mutant Strains Molecular Chaperones / physiology* Neovascularization, Pathologic / physiopathology Neovascularization, Physiologic / physiology* Nuclear Proteins / physiology Oxygen / pharmacology Protein Transport Proteins / genetics Proteins / physiology* RNA, Antisense / pharmacology RNA, Messenger / metabolism Rats Recombinant Fusion Proteins / physiology Single-Blind Method Skin / blood supply Skin / injuries Transcription Factors* Transforming Growth Factor beta / physiology Transforming Growth Factor beta1 Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors Wound Healing / physiology
IF 12.282
Times Cited 118
WOS Category MEDICINE, RESEARCH & EXPERIMENTAL
Resource
DNA material AxCALacZ (RDB01745) Ax1 CA gfp (RDB01727)