GM-CSF induces expression of soluble VEGF receptor-1 from human monocytes and inhibits angiogenesis in mice.
GM-CSF promotes homeostasis of myeloid cells. We report that GM-CSF upregulates mRNA and protein production of the soluble form of membrane bound VEGF receptor-1 (sVEGFR-1) in human monocytes. This sVEGFR-1 was biologically active, as cell-free supernatants from GM-CSF-stimulated monocytes blocked detection of endogenously expressed VEGF and inhibited endothelial cell migration and tube formation, even in the presence of exogenous rhVEGF. VEGF activity was recovered by neutralizing sVEGFR-1. To determine whether these events were important in vivo, Matrigel plugs were incubated with rhVEGF, rhGM-CSF, or rhGM-CSF/rhVEGF and injected into mice. Plugs containing GM-CSF or GM-CSF/VEGF had less endothelial cell invasion than plugs containing rhVEGF and were similar to plugs incubated with PBS alone. Neutralizing antibodies specific for sVEGFR-1 injected in these plugs reversed the effects of GM-CSF or GM-CSF/VEGF, while an isogenic antibody did not. Thus, GM-CSF and monocytes play a vital role in angiogenesis through the regulation of VEGF and sVEGFR-1.
Eubank
Tim D
TD
The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA.
Roberts
Ryan
R
Galloway
Michelle
M
Wang
Yijie
Y
Cohn
David E
DE
Marsh
Clay B
CB
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000737:chemistry; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053614:Janus Kinase 2; D007797:Laminin / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009500:Neutralization Tests; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D012995:Solubility; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; D017077:Culture Media, Conditioned; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D048031:JNK Mitogen-Activated Protein Kinases