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From the Department of Anatomy, Cell Biology & Injury Sciences, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey
Murine thioglycolate-induced peritoneal macrophages (MPMs) and the
murine RAW264.7 macrophage-like cell line (RAW cells) constitutively
produce vascular endothelial growth factor (VEGF). VEGF production is
increased under hypoxic conditions or after cell activation with
interferon-
(IFN) and endotoxin (lipopolysaccharide,
LPS). In contrast, tumor necrosis factor-
is produced only
by IFN/LPS-activated cells. Lactate (25 mmol/L) does not increase
VEGF production by these cells. However, hypoxia,
lactate, and IFN/LPS-activated MPMs express angiogenic
activity, whereas normoxic, nonactivated MPMs do not.
Lack of angiogenic activity is not due to an antiangiogenic factor(s)
in the medium of these cells. Angiogenic activity produced by hypoxia
and lactate-treated MPMs is neutralized by anti-VEGF antibody,
which also neutralizes most of the angiogenic activity produced by
IFN/LPS-activated MPMs. The inducible nitric oxide synthase
inhibitors
Ng-nitro-L-arginine-methyl ester
(1.5 mmol/L) and aminoguanidine (1 mmol/L) block production of
angiogenic activity by MPMs and RAW cells. In RAW cells,
Ng-nitro-L-arginine-methyl ester
and AG block IFN/LPS-activated, but not
constitutive, VEGF production, whereas in MPMs,
neither constitutive nor IFN/LPS-activated VEGF synthesis is
affected. Synthesis of tumor necrosis factor- is also unaffected. In
contrast to normoxic, nonactivated MPMs, inducible
nitric oxide synthase-inhibited, IFN/LPS-activated MPMs
produce an antiangiogenic factor(s). We conclude that VEGF is a major
contributor to macrophage-derived angiogenic activity, and that
activation by hypoxia, lactate, or IFN/LPS switches
macrophage-derived VEGF from a nonangiogenic to an angiogenic state.
This switch may involve a posttranslational modification of
VEGF, possibly by the process of ADP-ribosylation.
ADP-ribosylation by MPM cytosolic extracts or by cholera toxin switches
rVEGF165 from an angiogenic to a nonangiogenic state. In
IFN/LPS-activated MPMs, the inducible nitric oxide
synthase-dependent pathway also regulates the expression of an
antiangiogenic factor(s) that antagonizes the bioactivity of VEGF and
provides an additional regulatory pathway controlling the angiogenic
phenotype of macrophages.
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