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First published online March 12, 2004
doi: 10.1242/10.1242/jcs.00999
Research Article |
1 Department of Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Dag Hammarskjöldsv. 20, 751 85 Uppsala, Sweden
2 ImClone Systems Incorporated, 180 Varick Street, New York, NY 10014, USA
* Author for correspondence (e-mail: Lena.Welsh{at}genpat.uu.se)
Accepted 13 November 2003
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.
Key words: Vasculogenesis, Angiogenesis, Embryoid body, Hemostasis, Thrombosis, Development, FGFR-1, VEGFR-2
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