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Expression of the oxygen-regulated protein ORP150 accelerates wound healing by modulating intracellular VEGF transport
Kentaro Ozawa, … , Satoshi Ogawa, Tohru Ohshima
Kentaro Ozawa, … , Satoshi Ogawa, Tohru Ohshima
Published July 1, 2001
Citation Information: J Clin Invest. 2001;108(1):41-50. https://doi.org/10.1172/JCI11772.
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Article

Expression of the oxygen-regulated protein ORP150 accelerates wound healing by modulating intracellular VEGF transport

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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.

Authors

Kentaro Ozawa, Toshikazu Kondo, Osamu Hori, Yasuko Kitao, David M. Stern, Wolfgang Eisenmenger, Satoshi Ogawa, Tohru Ohshima

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Figure 1

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ORP150 expression in healing human wound. (a–e) A human wound (31-year-o...
ORP150 expression in healing human wound. (a–e) A human wound (31-year-old male) was analyzed either by H&E staining (×2) (the area indicated by open box was further studied in b–k) or immunohistochemically using anti-ORP150 (×40) (b), anti-CD68 Ab (×40) (c), anti-VEGF Ab (×40) (d), or anti-CD31 Ab (×40) (e), followed by visualization with the peroxidase method. (f–h) Sections adjacent to b (areas indicated by filled arrowheads) were double-stained with anti-ORP150 Ab (f) and anti-CD68 Ab (g). Both images were digitally overlapped (×100) (h). (i–k) Sections adjacent to f were double-stained with anti-ORP150 Ab (i) and anti-VEGF Ab (j). Both images were digitally overlapped (×100) (k). Open arrowheads in a denote the edge of the granulation tissue. See text for the description of filled arrowheads in b–e.

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