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

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 approximately 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.

[1]  G. Semenza,et al.  General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[2]  P. Ratcliffe,et al.  Inducible operation of the erythropoietin 3' enhancer in multiple cell lines: evidence for a widespread oxygen-sensing mechanism. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[3]  D. Pinsky,et al.  Hypoxia-mediated induction of endothelial cell interleukin-1 alpha. An autocrine mechanism promoting expression of leukocyte adhesion molecules on the vessel surface. , 1992, The Journal of clinical investigation.

[4]  Y. Koga,et al.  Synthesis and release of interleukin 1 by reoxygenated human mononuclear phagocytes. , 1992, The Journal of clinical investigation.

[5]  R. Weinmann,et al.  Enhancer element at the 3'-flanking region controls transcriptional response to hypoxia in the human erythropoietin gene. , 1991, The Journal of biological chemistry.

[6]  H. Lieberman,et al.  Macrovascular and microvascular endothelium during long‐term hypoxia: Alterations in cell growth, monolayer permeability, and cell surface coagulant properties , 1991, Journal of cellular physiology.

[7]  M. Jaye,et al.  Cloning and expression of two distinct high‐affinity receptors cross‐reacting with acidic and basic fibroblast growth factors. , 1990, The EMBO journal.

[8]  D. Goeddel,et al.  Vascular endothelial growth factor is a secreted angiogenic mitogen. , 1989, Science.

[9]  A. Haimovitz-Friedman,et al.  Effects of irradiation on the release of growth factors from cultured bovine, porcine, and human endothelial cells. , 1989, Cancer research.

[10]  D. Hanahan,et al.  Induction of angiogenesis during the transition from hyperplasia to neoplasia , 1989, Nature.

[11]  M. Goldberg,et al.  Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein. , 1988, Science.

[12]  D. Moscatelli,et al.  The development of a quantitative RIA for basic fibroblast growth factor using polyclonal antibodies against the 157 amino acid form of human bFGF. The identification of bFGF in adherent elicited murine peritoneal macrophages. , 1988, Journal of immunological methods.

[13]  P. Delli Bovi,et al.  Isolation of a rearranged human transforming gene following transfection of Kaposi sarcoma DNA. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[14]  D. Moscatelli,et al.  High and low affinity binding sites for basic fibroblast growth factor on cultured cells: Absence of a role for low affinity binding in the stimulation of plasminogen activator production by bovine capillary endothelial cells , 1987, Journal of cellular physiology.

[15]  B. Olwin,et al.  Identification of the fibroblast growth factor receptor of Swiss 3T3 cells and mouse skeletal muscle myoblasts. , 1986, Biochemistry.

[16]  R. Alexander,et al.  Nonlinear relationship between alpha 1-adrenergic receptor occupancy and norepinephrine-stimulated calcium flux in cultured vascular smooth muscle cells. , 1985, Molecular pharmacology.

[17]  F. Alt,et al.  Developmentally controlled and tissue-specific expression of unrearranged VH gene segments , 1985, Cell.

[18]  T. K. Hunt,et al.  Oxygen tension regulates the expression of angiogenesis factor by macrophages. , 1983, Science.

[19]  W. Rutter,et al.  Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. , 1979, Biochemistry.

[20]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[21]  M. Reidy,et al.  Basic Fibroblast Growth Factor Stimulates Endothelial Regrowth and Proliferation in Denuded Arteries , 2022 .