Emerging roles of the Angiopoietin-Tie and the ephrin-Eph systems as regulators of cell trafficking.

Vascular receptor tyrosine kinases (RTK) have been identified as critical regulatory signaling molecules of developmental and adult vascular morphogenic processes [vascular endothelial growth factor (VEGF) receptors=sprouting; EphB receptors=assembly; Tie2 receptor=maturation and quiescence]. It is intriguing that the same molecules that control the growth of blood and lymphatic vessels play critical roles in the adult to regulate maintenance functions related to vascular homeostasis. VEGF is among the most potent inducers of vascular permeability. The second vascular RTK system, the interaction of paracrine-acting Angiopoietin-1 with its cognate receptor Tie2, acts as an endothelial maintenance and survival-mediating molecular system, which stabilizes the vessel wall and controls endothelial cell quiescence. The third vascular RTK system, the interaction of Eph receptors with their Eph family receptor-interacting protein (ephrin) ligands, transduces positional guidance cues on outgrowing vascular sprouts, which are critical for proper arteriovenous assembly and establishment of blood flow. As such, Eph-ephrin interactions act as an important regulator of cell-cell interactions, exerting propulsive and repulsive functions on neighboring cells and mediating adhesive functions. This review summarizes recent findings related to the roles of the Angiopoietin-Tie and the Eph-ephrin systems as regulators of cell trafficking in the vascular system. The recognition of vascular homeostatic functions of vascular RTKs marks an important change of paradigm in the field of angiogenesis research as it relates angiogenesis-inducing molecules to vascular maintenance functions in the adult. This may also broaden the scope of vascular RTK-targeted therapies.