EphrinB reverse signaling contributes to endothelial and mural cell assembly into vascular structures.
EphrinB transmembrane ligands and their cognate EphB receptor tyrosine kinases regulate vascular development through bidirectional cell-to-cell signaling, but little is known about the role of EphrinB during postnatal vascular remodeling. We report that EphrinB is a critical mediator of postnatal pericyte-to-endothelial cell assembly into vascular structures. This function is dependent upon extracellular matrix-supported cell-to-cell contact, engagement of EphrinB by EphB receptors expressed on another cell, and Src-dependent phosphorylation of the intracytoplasmic domain of EphrinB. Phosphorylated EphrinB marks angiogenic blood vessels in the developing and hypoxic retina, the wounded skin, and tumor tissue, and is detected at contact points between endothelial cells and pericytes. Furthermore, inhibition ofEphrinB activity prevents proper assembly of pericytes and endothelial cells into vascular structures. These results reveal a role for EphrinB signaling in orchestrating pericyte/endothelial cell assembly, and suggest that therapeutic targeting of EphrinB may prove useful for disrupting angiogenesis when it contributes to disease.
Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. salvucco@mail.nih.gov
Ombretta
O
Salvucci
Dragan
D
Maric
Matina
M
Economopoulou
Shuhei
S
Sakakibara
Simone
S
Merlin
Antonia
A
Follenzi
Giovanna
G
Tosato
D000818:Animals; D000831:Animals, Newborn; D001808:Blood Vessels / Q000254:growth & development* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000502:physiology; D002448:Cell Adhesion / Q000235:genetics; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D036388:Ephrin-B2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D036342:Ephrins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D020286:Pericytes / Q000378:metabolism / Q000502:physiology*; D036081:Receptors, Eph Family / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D036388:Ephrin-B2; D036342:Ephrins; D036081:Receptors, Eph Family