Hypoxia-mediated induction of acidic/basic fibroblast growth factor and platelet-derived growth factor in mononuclear phagocytes stimulates growth of hypoxic endothelial cells

Keisuke Kuwabara, Satoshi Ogawa, Masayasu Matsumoto, Shin Koga, Matthias Clauss, David J. Pinsky, Peter Lyn, Jeffrey Leavy, Larry Witte, Jacqueline Joseph-Silverstein, Martha B. Furie, Gabriella Torcia, Federico Cozzolino, Takenobu Kamada, David M. Stern

Research output: Contribution to journalArticle

218 Scopus citations

Abstract

Wound repair and tumor vascularization depend upon blood vessel growth into hypoxic tissue. Although hypoxia slows endothelial cell (EC) proliferation and suppresses EC basic fibroblast growth factor (bFGF) expression, we report that macrophages (MPs) exposed to PO2 ≃ 12-14 torr (1 torr = 133.3 Pa) synthesize and release in a time-dependent manner platelet- derived growth factor (PDGF) and acidic/basic FGFs (a/bFGFs), which stimulate the growth of hypoxic ECs. Chromatography of hypoxic MP-conditioned medium on immobilized heparin with an ascending NaCl gradient resolved three peaks of mitogenic activity: activity of the first peak was neutralized by antibody to PDGF; activity of the second peak was neutralized by antibody to aFGF; and activity of the third peak was neutralized by antibody to bFGF. Metabolically labeled lysates and supernatants from MPs exposed to hypoxia showed increased synthesis and release of immunoprecipitable PDGF and a/bFGF in the absence of changes in cell viability. Possible involvement of a heme-containing oxygen sensor in MP elaboration of growth factors was suggested by the induction of bFGF and PDGF by normoxic MPs exposed to nickel or cobalt, although metabolic inhibitors such as sodium azide were without effect. These results suggest a paracrine model in which hypoxia stimulates MP release of PDGF and a/bFGF, inducing EC proliferation and potentially promoting angiogenesis in hypoxic environments.

Original languageEnglish (US)
Pages (from-to)4606-4610
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number10
DOIs
StatePublished - May 9 1995
Externally publishedYes

Keywords

  • angiogenesis
  • endothelium

ASJC Scopus subject areas

  • General

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    Kuwabara, K., Ogawa, S., Matsumoto, M., Koga, S., Clauss, M., Pinsky, D. J., Lyn, P., Leavy, J., Witte, L., Joseph-Silverstein, J., Furie, M. B., Torcia, G., Cozzolino, F., Kamada, T., & Stern, D. M. (1995). Hypoxia-mediated induction of acidic/basic fibroblast growth factor and platelet-derived growth factor in mononuclear phagocytes stimulates growth of hypoxic endothelial cells. Proceedings of the National Academy of Sciences of the United States of America, 92(10), 4606-4610. https://doi.org/10.1073/pnas.92.10.4606