EphB4 controls blood vascular morphogenesis during postnatal angiogenesis
EphB4 controls blood vascular morphogenesis during postnatal angiogenesis
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DOI：
10.1038/sj.emboj.7600949
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发表时间：
2006-02-08
期刊：
影响因子：
11.4
通讯作者：
Vajkoczy, P
中科院分区：
文献类型：
--
作者：
Erber, R;Eichelsbacher, U;Vajkoczy, P
引导分子通过证明它们在发育过程中调节血管系统的模式而引起了人们的兴趣。然而，它们在出生后血管生成过程中的意义仍然未知。在这里，我们证明了人类恶性脑肿瘤的内皮细胞也表达导向分子，如EphB 4及其配体ephrinB 2。为了研究它们的功能，EphB 4变体在肿瘤异种移植物的血管中过表达。我们的研究表明，EphB 4作为血管分支和血管网络形成的负调节剂，将血管形成程序从萌芽血管生成转换为周向血管生长。同时，EphB 4通过在内皮/周细胞界面激活血管生成素-1/Tie2系统降低肿瘤血管系统的渗透性。此外，在（i）非肿瘤性细胞移植物的血管形成和（ii）视网膜血管形成期间血管中EphB 4变体的过表达揭示了EphB 4的这些功能一般适用于出生后的非肿瘤性血管生成。这意味着肿瘤性和非肿瘤性血管形成不仅由血管起始程序驱动，而且还由引导分子介导的血管图案化程序驱动。
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.