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PMID:12734395

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Citation

Füller, T, Korff, T, Kilian, A, Dandekar, G and Augustin, HG (2003) Forward EphB4 signaling in endothelial cells controls cellular repulsion and segregation from ephrinB2 positive cells. J. Cell. Sci. 116:2461-70

Abstract

Contact-dependent interactions between endothelial cells (ECs), as well as between ECs and mural cells, play a key role in the formation of a regular vascular system and the assembly of the vessel wall. Recent studies have identified ephrinB2 and EphB4 as markers and makers of arteriovenous differentiation during vascular development. On the basis of these findings, we hypothesized that Ephephrin interactions in the vascular system mediate distinct propulsive and repulsive effector functions that provide guidance signals for the proper spatial organization of the developing vasculature. Utilizing a set of specialized endothelial differentiation and angiogenesis assays, the present study was aimed at studying vascular morphogenic functions of endothelial EphB4 and ephrinB2 activation. EphrinB2-Fc acts anti-adhesively and induces detachment of ECs, as demonstrated by (1) inhibition of adhesion to ephrinB2-Fc-coated culture dishes, (2) detachment of ECs grown as differentiated 3D spheroids, and (3) endothelial denudation of explanted fragments of umbilical vein. Conversely, soluble ephrinB2-Fc inhibits lateral cell migration, vascular endothelial growth factor (VEGF) gradient-driven chemotaxis, capillary-like network formation and sprouting angiogenesis. In turn, soluble EphB4-Fc is pro-adhesive and stimulates EC migration and sprouting angiogenesis. EphrinB2-mediated repulsive signals are transduced by EphB4, as demonstrated by EphrinB2-Fc inhibition of sprouting angiogenesis of constitutively EphB4-overexpressing ECs. Confrontation experiments of EphB4-overexpressing ECs with ECs overexpressing full-length or truncated ephrinB2 that lacks the cytoplasmic catalytic domain demonstrated that forward EphB4 signaling with EphB4 tyrosine phosphorylation restricts intermingling of cells and supports cellular segregation. Taken together, these data identify distinct propulsive and repulsive effector functions of endothelial ephrinB2 and EphB4 that mediate spatial positional signals during angiogenesis and vessel assembly.

Links

PubMed Online version:10.1242/jcs.00426

Keywords

Capillaries/cytology; Capillaries/growth & development; Capillaries/metabolism; Catalytic Domain/drug effects; Catalytic Domain/physiology; Cell Adhesion/drug effects; Cell Adhesion/physiology; Cell Communication/drug effects; Cell Communication/physiology; Cell Differentiation/drug effects; Cell Differentiation/physiology; Cells, Cultured; Chemotaxis/drug effects; Chemotaxis/physiology; Coculture Techniques; Cues; Endothelial Cells/cytology; Endothelial Cells/drug effects; Endothelial Cells/metabolism; Ephrin-B2/agonists; Ephrin-B2/metabolism; Humans; Muscle, Smooth, Vascular/cytology; Neovascularization, Physiologic/drug effects; Neovascularization, Physiologic/physiology; Phosphorylation/drug effects; Receptor, EphB4/agonists; Receptor, EphB4/metabolism; Recombinant Fusion Proteins/pharmacology; Signal Transduction/drug effects; Signal Transduction/physiology; Spheroids, Cellular/cytology; Spheroids, Cellular/drug effects; Spheroids, Cellular/metabolism; Umbilical Veins/cytology; Umbilical Veins/growth & development; Umbilical Veins/metabolism; Vascular Endothelial Growth Factor A/antagonists & inhibitors

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:EFNB2

involved_in

GO:0002042: cell migration involved in sprouting angiogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EFNB2

involved_in

GO:0007155: cell adhesion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EFNB2

involved_in

GO:0050920: regulation of chemotaxis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EFNB2

involved_in

GO:0048013: ephrin receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EPHB4

involved_in

GO:0048013: ephrin receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EPHB4

involved_in

GO:0007155: cell adhesion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EPHB4

enables

GO:0005003: ephrin receptor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:EPHB4

involved_in

GO:0002042: cell migration involved in sprouting angiogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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