Submitted November 23, 2005
Accepted June 27, 2006
EphB2 and EphB4 receptors forward signaling promotes SDF-
1-induced endothelial cell chemotaxis and branching
remodeling
Ombretta Salvucci, Maria De La Luz Sierra, Jose A Martina, Peter J McCormick, and Giovanna Tosato*
Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD
Laboratory of Cell Biology, National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA
* Corresponding author; email: tosatog{at}mail.nih.gov.
The complex molecular mechanisms that drive endothelial
cell movement and formation of new vessels are poorly
understood and require further investigation. Eph
receptors tyrosine kinases and their membrane-anchored
ephrin ligands regulate cell movements mostly by cell-to-
cell contact, whereas the G-protein-coupled receptor
CXCR4 and its unique SDF-1 chemokine ligand regulate
cell movement mostly through soluble gradients. Here,
by using biochemical and functional approaches, we
investigated how ephrinB and SDF-1 orchestrate
endothelial cell movement and morphogenesis into
capillary-like structures. We describe that in primary
human endothelial cells endogenous EphB2 and EphB4
signaling is required for the formation of extracellular
matrix-dependent capillary-like structures. We further
demonstrate that EphB2 and EphB4 activation enhances SDF-
1-induced signaling and chemotaxis that are also
required for extracellular matrix-dependent endothelial
cell clustering. These results support a model in which
SDF-1 gradients first promote endothelial cell
clustering, and EphB2 and EphB4 critically contribute to
subsequent cell movement and alignment into cord-like
structures. This study reveals a requirement for
endogenous Eph signaling in endothelial cell morphogenic
processes, uncovers a novel link between EphB forward
signaling and SDF-1-induced signaling, and demonstrates
a mechanism for cooperative regulation of endothelial
cell movement.
