Control of vascular morphogenesis by Eph receptor and ephrin signaling
Receptor tyrosine kinases (RTKs) are well-established regulators of morphogenic processes during vertebrate embryonic development. Their signaling controls a multitude of fundamental cellular processes including proliferation, differentiation, protection against cell death and guidance of migrating cells or neuronal growth cones (Flanagan and Vanderhaeghen, 1998; Holder et al., 1999; Huang et al., 2001; Schlessinger, 2000). In the cardiovascular system, crucial roles for RTKs binding soluble ligands, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and angiopoietin, have been firmly established (Gale and Yancopoulos, 1999; Risau and Flamme, 1995). Among other functions, some of these molecules regulate the de novo assembly of blood vessels (vasculogenesis) and their branching into complex networks (angiogenesis), processes by which the vascular system is initially formed in embryos and subsequently expanded and adapted to match the increasing requirements of growing tissues (Flamme et al., 1997). More recently, the molecular repertoire controlling vascular growth and organization has been expanded to include the large RTK family of Eph receptors (named for the expression of the founding molecule in an erythropoietin-producing hepatocel-lular carcinoma cell line) and their ligands, called ephrins (for Eph receptor inter-acting molecules) (EN Committee, 1997). Unlike soluble growth factors, ephrins are cell surface-attached molecules and require direct cell-cell contact for interaction with Eph receptors. Their most remarkable feature is the unusual ability of ephrin molecules to induce bidirectional signal transduction into both ligandand receptor-expressing cells. The Eph/ephrin system provides a complex and, because of the large number of genes involved, costly signaling tool kit used not only in the vasculature but in a wide range of body structures. The previously described functions of the gene family in the developing nervous system also encourages speculation about 18possible parallels or links between neuronal and vascular network formation (Shima et al., 2000).