Notch receptor expression in human brain arteriovenous malformations

Abstract

The roles of the Notch pathway proteins in normal adult vascular physiology and the pathogenesis of brain arteriovenous malformations are not well-understood. Notch 1 and 4 have been detected in human and mutant mice vascular malformations respectively. Although mutations in the human Notch 3 gene caused a genetic form of vascular stroke and dementia, its role in arteriovenous malformations development has been unknown. In this study, we performed immunohistochemistry screening on tissue microarrays containing eight surgically resected human brain arteriovenous malformations and 10 control surgical epilepsy samples. The tissue microarrays were evaluated for Notch 1–4 expression. We have found that compared to normal brain vascular tissue Notch-3 was dramatically increased in brain arteriovenous malformations. Similarly, Notch 4 labelling was also increased in vascular malformations and was confirmed by western blot analysis. Notch 2 was not detectable in any of the human vessels analysed. Using both immunohistochemistry on microarrays and western blot analysis, we have found that Notch-1 expression was detectable in control vessels, and discovered a significant decrease of Notch 1 expression in vascular malformations. We have demonstrated that Notch 3 and 4, and not Notch 1, were highly increased in human arteriovenous malformations. Our findings suggested that Notch 4, and more importantly, Notch 3, may play a role in the development and pathobiology of human arteriovenous malformations.

Notch signaling pathway is a potential therapeutic target for extracranial vascular malformations

“…Human brain AVMs have disrupted elastin fibers, which compromise the structural integrity of the vessel and mediate arteriovenous malformations 19–21 . While brain elastin content has been well characterized, the elastin in extracranial vascular malformation has not been studied.…”

Notch signaling pathway regulates cell cycle in proliferating hepatocytes involved in liver regeneration

“…Notch signaling pathway played a key role in liver homeostasis, metabolism, regeneration, vascular physiology, and reparative morphogenesis of the biliary tree . However, it was difficult to distinguish whether it was hepatocytes, biliary epithelial cells, or sinusoidal endothelial cells specificity of Notch signaling that played crucial role.…”

Gene expression analysis of nidus of cerebral arteriovenous malformations reveals vascular structures with deficient differentiation and maturation

“…In our study, we observed an augmented expression of EphrinB2, Hey2 and Dll4 in the nidus structures from patients with cerebral AVM when compared to normal brain arteries. Previous studies have reported that Notch-1 and Notch-3 are over expressed in AVM nidus [ 32 – 34 ]. Together our findings suggest that a deregulated arterial specification signaling might have a significant role in the pathogenesis of AVM.…”

“…Previous studies had identified that endothelial cell of AVM vessels expresses either artery or vein marker [ 32 , 33 , 34 ]. Co-expression of both artery-specific genes HEY2 , DLL4 , EFNB2 and vein specific gene COUP-TFII in endothelial cells of AVM vessels as observed in our study is a novel finding.…”