Expression of the oxygen-regulated protein ORP150 accelerates wound healing by modulating intracellular VEGF transport.
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.
Ozawa
K
K
Department of Neuroanatomy, Faculty of Medicine, Kanazawa University, Kanazawa City, Ishikawa, Japan. ozawa@nanat.m.kanazawa-u.ac.jp
Kondo
T
T
Hori
O
O
Kitao
Y
Y
Stern
D M
DM
Eisenmenger
W
W
Ogawa
S
S
Ohshima
T
T
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins / Q000502:physiology; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018832:Molecular Chaperones / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology; D010100:Oxygen / Q000494:pharmacology; D021381:Protein Transport; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D016372:RNA, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016037:Single-Blind Method; D012867:Skin / Q000098:blood supply / Q000293:injuries; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000502:physiology; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014945:Wound Healing / Q000502:physiology
D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C497442:HIF1A protein, human; D018840:HSP70 Heat-Shock Proteins; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D011506:Proteins; D016372:RNA, Antisense; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C050087:oxygen-regulated proteins; D016222:Fibroblast Growth Factor 2; D010100:Oxygen