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.
Highlights
Brain arteriovenous malformations (BAVM) are abnormal vascular structures caused by the replacement of normal capillary beds with enlarged and tangled vessels
In this study using tissue microarrays (TMAs), we evaluated the expression of Notch receptor proteins (1–4) in human brain AVMs as compared to control human vessels harvested from patients during epilepsy surgery
To screen the levels of Notch 1–4 proteins in human BAVMs and control vessels, we performed immunohistochemistry using specific Notch antibodies on a TMA to simultaneously allow labelling and analyses of the entire retrospective cohort
Summary
Brain arteriovenous malformations (BAVM) are abnormal vascular structures caused by the replacement of normal capillary beds with enlarged and tangled vessels. The lesions are thought to be congenital in origin, and the overwhelming majority of cases are sporadic. These rare lesions can lead to increased blood flow and high pressure in the vessels that can lead to the dilation of feeder arteries and veins. This dilation weakens the vessels making them susceptible to haemorrhage [1]. Brain arteriovenous malformations are often asymptomatic, but symptomatic patients present with headaches, seizures and haemorrhage, potentially leading to potential significant neurological impairment or death.
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