title: Regulation of signaling interactions and receptor endocytosis in growing blood vessels.
abstract: Blood vessels and the lymphatic vasculature are extensive tubular networks formed by endothelial cells that have several indispensable functions in the developing and adult organism. During growth and tissue regeneration but also in many pathological settings, these vascular networks expand, which is critically controlled by the receptor EphB4 and the ligand ephrin-B2. An increasing body of evidence links Eph/ephrin molecules to the function of other receptor tyrosine kinases and cell surface receptors. In the endothelium, ephrin-B2 is required for clathrin-dependent internalization and full signaling activity of VEGFR2, the main receptor for vascular endothelial growth factor. In vascular smooth muscle cells, ephrin-B2 antagonizes clathrin-dependent endocytosis of PDGFRβ and controls the balanced activation of different signal transduction processes after stimulation with platelet-derived growth factor. This review summarizes the important roles of Eph/ephrin molecules in vascular morphogenesis and explains the function of ephrin-B2 as a molecular hub for receptor endocytosis in the vasculature.
authors.affiliation: a Department of Tissue Morphogenesis; Max Planck Institute for Molecular Biomedicine; and Faculty of Medicine , University of Münster ; Münster , Germany.
authors.forename: Mara E
authors.initials: ME
authors.lastname: Pitulescu
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000254:growth & development*; D004705:Endocytosis; D042783:Endothelial Cells / Q000502:physiology; D036388:Ephrin-B2 / Q000378:metabolism*; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000473:pathology; D051379:Mice; D009024:Morphogenesis; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D036224:Receptor, EphB4 / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D015027:Zebrafish
chemical_list: D036388:Ephrin-B2; D020794:Receptor Protein-Tyrosine Kinases; D036224:Receptor, EphB4; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Ang, angiopoietin; CHC, clathrin heavy chains; CLASP, clathrin-associated-sorting protein; CV, cardinal vein; DA, dorsal aorta; EC, endothelial cell; EEA1, early antigen 1; Eph; Ephrin-B2ΔV, ephrin-B2 deletion of C-terminal PDZ binding motif; HSPG, heparan sulfate proteoglycan; JNK, c-Jun N-terminal kinase; LEC, lymphatic endothelial cells; LRP1, Low density lipoprotein receptor-related protein 1; MVB, multivesicular body; NRP, neuropilin; PC, pericytes; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; PTC, peritubular capillary; PlGF, placental growth factor; RTK, receptor tyrosine kinase; VEGF, Vascular endothelial growth factor; VEGFR, Vascular endothelial growth factor receptor; VSMC, vascular smooth muscle cells.; aPKC, atypical protein kinase C; endocytosis; endothelial cells; ephrin; mural cells; receptor