EphB4 controls blood vascular morphogenesis during postnatal angiogenesis.
Guidance molecules have attracted interest by demonstration that they regulate patterning of the blood vascular system during development. However, their significance during postnatal angiogenesis has remained unknown. Here, we demonstrate that endothelial cells of human malignant brain tumors also express guidance molecules, such as EphB4 and its ligand ephrinB2. To study their function, EphB4 variants were overexpressed in blood vessels of tumor xenografts. Our studies revealed that EphB4 acts as a negative regulator of blood vessel branching and vascular network formation, switching the vascularization program from sprouting angiogenesis to circumferential vessel growth. In parallel, EphB4 reduces the permeability of the tumor vascular system via activation of the angiopoietin-1/Tie2 system at the endothelium/pericyte interface. Furthermore, overexpression of EphB4 variants in blood vessels during (i) vascularization of non-neoplastic cell grafts and (ii) retinal vascularization revealed that these functions of EphB4 apply to postnatal, non-neoplastic angiogenesis in general. This implies that both neoplastic and non-neoplastic vascularization is driven not only by a vascular initiation program but also by a vascular patterning program mediated by guidance molecules.
Erber
Ralf
R
Department of Neurosurgery, Faculty for Clinical Medicine of the University of Heidelberg, University Hospital Mannheim, Mannheim, Germany.
Eichelsbacher
Uta
U
Powajbo
Violetta
V
Korn
Tobias
T
Djonov
Valentin
V
Lin
Jihong
J
Hammes
Hans-Peter
HP
Grobholz
Rainer
R
Ullrich
Axel
A
Vajkoczy
Peter
P
D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000378:metabolism; D002199:Capillary Permeability; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism; D036388:Ephrin-B2 / Q000096:biosynthesis; D005910:Glioma / Q000098:blood supply / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009024:Morphogenesis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D036224:Receptor, EphB4 / Q000096:biosynthesis / Q000502:physiology*; D042787:Receptor, TIE-2 / Q000378:metabolism; D012171:Retinal Vessels / Q000254:growth & development; D015398:Signal Transduction; D014183:Transplantation, Heterologous
D042683:Angiopoietin-1; D036388:Ephrin-B2; D036224:Receptor, EphB4; D042787:Receptor, TIE-2