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 Blood, 20 August 2009, Vol. 114, No. 8, pp. 1707-1716.
Prepublished online as a Blood First Edition Paper on May 1, 2009; DOI 10.1182/blood-2008-12-192294.

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VASCULAR BIOLOGY

EphrinB reverse signaling contributes to endothelial and mural cell assembly into vascular structures

Ombretta Salvucci1, Dragan Maric2, Matina Economopoulou1, Shuhei Sakakibara1, Simone Merlin3, Antonia Follenzi3,4, and Giovanna Tosato1

1 Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, and 2 Laboratory of Neurophysiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda MD; 3 Department of Medical Sciences, University of Piemonte Orientale School of Medicine, Novara, Italy; and 4 Department of Pathology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, New York, NY

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.


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