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Vol. 13, No. 3, pp. 295-306, February 1, 1999
1 European Molecular Biology Laboratory, D-69117
Heidelberg, Germany; 2 Max-Planck-Institute for
Physiological and Clinical Research, W.G. Kerckhoff Institute, 61231 Bad Nauheim, Germany; 3 Regeneron Pharmaceuticals, Inc.,
Tarrytown, New York 10591 USA
Eph receptor tyrosine kinases and their cell-surface-bound ligands,
the ephrins, regulate axon guidance and bundling in the developing
brain, control cell migration and adhesion, and help patterning the
embryo. Here we report that two ephrinB ligands and three EphB
receptors are expressed in and regulate the formation of the vascular
network. Mice lacking ephrinB2 and a proportion of double mutants
deficient in EphB2 and EphB3 receptor signaling die in utero before
embryonic day 11.5 (E11.5) because of defects in the remodeling of the
embryonic vascular system. Our phenotypic analysis suggests complex
interactions and multiple functions of Eph receptors and ephrins in the
embryonic vasculature. Interaction between ephrinB2 on arteries and its
EphB receptors on veins suggests a role in defining boundaries between
arterial and venous domains. Expression of ephrinB1 by arterial and
venous endothelial cells and EphB3 by veins and some arteries indicates
that endothelial cell-to-cell interactions between ephrins and Eph
receptors are not restricted to the border between arteries and veins.
Furthermore, expression of ephrinB2 and EphB2 in mesenchyme adjacent to
vessels and vascular defects in ephB2/ephB3
double mutants indicate a requirement for ephrin-Eph signaling between
endothelial cells and surrounding mesenchymal cells. Finally, ephrinB
ligands induce capillary sprouting in vitro with a similar efficiency
as angiopoietin-1 (Ang1) and vascular endothelial growth factor (VEGF),
demonstrating a stimulatory role of ephrins in the remodeling of the
developing vascular system.
[Key Words: Angiogenesis; ephrins; Eph; receptor tyrosine kinase; vasculogenesis]
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