Abstract
We have employed embryoid bodies derived from murine embryonal stem cells to study effects on vascular development induced by fibroblast growth factor (FGF)-2 and FGF receptor-1, in comparison to the established angiogenic factor vascular endothelial growth factor (VEGF)-A and its receptor VEGF receptor-2. Exogenous FGF-2 promoted formation of morphologically distinct, long slender vessels in the embryoid bodies, whereas VEGF-A-treated bodies displayed a compact plexus of capillaries. FGF-2 stimulation of embryonal stem cells under conditions where VEGF-A/VEGFR-2 function was blocked, led to formation of endothelial cell clusters, which failed to develop into vessels. FGFR-1(-/-) embryoid bodies responded to VEGF-A by establishment of the characteristic vascular plexus, but FGF-2 had no effect on vascular development in the absence of FGFR-1. The FGFR-1(-/-) embryoid bodies displayed considerably increased basal level of vessel formation, detected by immunohistochemical staining for platelet-endothelial cell adhesion molecule (PECAM)/CD31. This basal vascularization was blocked by neutralizing antibodies against VEGFR-2 or VEGF-A and biochemical analyses indicated changes in regulation of VEGFR-2 in the absence of FGFR-1 expression. We conclude that VEGF-A/VEGFR-2-dependent vessel formation occurs in the absence of FGF-2/FGFR-1, which, however, serve to modulate vascular development.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Blocking / pharmacology
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Antigens, CD
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Cadherins / metabolism
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Capillaries / drug effects
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Capillaries / growth & development
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Capillaries / metabolism
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Cells, Cultured
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Fibroblast Growth Factor 2 / pharmacology
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Fibroblast Growth Factor 2 / physiology*
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Fibroblasts / cytology
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Fibroblasts / physiology
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Immunohistochemistry
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Mice
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Mice, Inbred Strains
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Neovascularization, Physiologic
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Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
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Receptor Protein-Tyrosine Kinases / metabolism*
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Receptor Protein-Tyrosine Kinases / pharmacology
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Receptor Protein-Tyrosine Kinases / physiology*
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Receptor, Fibroblast Growth Factor, Type 1
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Receptors, Fibroblast Growth Factor / antagonists & inhibitors
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Receptors, Fibroblast Growth Factor / metabolism*
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Receptors, Fibroblast Growth Factor / physiology*
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Stem Cells / cytology
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Vascular Endothelial Growth Factor A / metabolism
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Vascular Endothelial Growth Factor A / pharmacology
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
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Vascular Endothelial Growth Factor Receptor-2 / metabolism*
Substances
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Antibodies, Blocking
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Antigens, CD
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Cadherins
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Platelet Endothelial Cell Adhesion Molecule-1
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Receptors, Fibroblast Growth Factor
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Vascular Endothelial Growth Factor A
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cadherin 5
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Fibroblast Growth Factor 2
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Fgfr1 protein, mouse
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Receptor Protein-Tyrosine Kinases
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Receptor, Fibroblast Growth Factor, Type 1
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Vascular Endothelial Growth Factor Receptor-2