Erber Ralf, Eichelsbacher Uta, Powajbo Violetta, Korn Tobias, Djonov Valentin, Lin Jihong, Hammes Hans-Peter, Grobholz Rainer, Ullrich Axel, Vajkoczy Peter
Department of Neurosurgery, Faculty for Clinical Medicine of the University of Heidelberg, University Hospital Mannheim, Mannheim, Germany.
EMBO J. 2006 Feb 8;25(3):628-41. doi: 10.1038/sj.emboj.7600949. Epub 2006 Jan 19.
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.
导向分子通过调控发育过程中血管系统的模式形成而受到关注。然而，它们在出生后血管生成中的意义仍不清楚。在此，我们证明人类恶性脑肿瘤的内皮细胞也表达导向分子，如EphB4及其配体ephrinB2。为了研究它们的功能，EphB4变体在肿瘤异种移植血管中过表达。我们的研究表明，EphB4作为血管分支和血管网络形成的负调节因子，将血管生成程序从芽生血管生成转变为周向血管生长。同时，EphB4通过在内皮细胞/周细胞界面激活血管生成素-1/Tie2系统来降低肿瘤血管系统的通透性。此外，在（i）非肿瘤细胞移植血管化和（ii）视网膜血管化过程中，EphB4变体在血管中的过表达表明，EphB4的这些功能通常适用于出生后的非肿瘤血管生成。这意味着肿瘤性和非肿瘤性血管生成不仅由血管起始程序驱动，还由导向分子介导的血管模式形成程序驱动。
