Ephrin B2 and EphB4 selectively mark arterial and venous vessels in cerebral arteriovenous malformation

Abstract

Objectives: Ephrin type B receptor 4 (EphB4, Eph receptor) selectively binds ephrin B2 (Eph ligand). EphB4/ephrin B2 is involved in embryonic vessel development, vascular remodelling and pathological vessel formation in adults (including tumour angiogenesis). Binding of vascular endothelial growth factor (VEGF)-A to the endothelial-specific receptor VEGF receptor-2 is the main extracellular signal triggering angiogenic response. Little is known about the role of EphB4/ephrin B2 during angiogenesis and arteriovenous plasticity in cerebral arteriovenous malformation (cAVM). This study investigated EphB4 and ephrin B2 expression in cAVM.

Methods: Haemorrhagic (H-AVM) and nonhaemorrhagic (NH-AVM) specimens of AVM nidus, obtained after microsurgical cAVM resection, and normal superficial temporal artery (STA) specimens, were analysed retrospectively. VEGF-A, EphB4 and ephrin B2 expression were studied by immunohistochemistry and immunoblotting.

Results: In cAVM (10 H-AVM; 10 NH-AVM), VEGF-A was immunocytochemically localized to endothelial cells; strong endothelial cell staining was found for EphB4 in veins and ephrin B2 in arteries. Normal STA (n = 10) did not express EphB4 or ephrin B2. EphB4 and ephrin B2 expression was greater in H-AVM than in NH-AVM.

Conclusions: Endothelial cells are more active in H-AVM than NH-AVM. EphB4 and ephrin B2 play important roles in neovascularization and arteriovenous differentiation/plasticity. These data provide new insights into the aetiology of cAVM and lay a foundation for further study. The notch pathway induced by VEGF-A may be a key signalling pathway in this process.

Keywords: Cerebral arteriovenous malformation; EphB4; arteriovenous plasticity; ephrin B2.