Abstract
ObjectiveArteriovenous malformations (AVMs) are characterised by tangles of dysplastic blood vessels which shunt blood from arteries to veins with no intervening capillary bed. It is not known at what stage of development and differentiation, AVM vessels became aberrant. To address this, we have analysed the expression of vascular differentiation, vascular maturation and brain capillary specific genes in AVM nidus.MethodologyWe performed immunohistochemistry and western blot analysis of vascular differentiation (HEY2, DLL4, EFNB2, and COUP-TFII), vascular maturation (ENG and KLF2) and brain capillary specific genes (GGTP and GLUT1) on ten surgically excised human brain AVMs and ten normal human brain tissues.ResultsImmunohistochemical analysis revealed that AVM vessels co-express both artery and vein differentiation genes. H-score analysis revealed that there is statistically significant (P < 0.0001) increase in expression of these proteins in AVM vessels compared to control vessels. These findings were further confirmed by western blot analysis and found to be statistically significant (P < 0.0001 and P < 0.001) for all proteins except Hey2. Both immunostaining and western blot analysis revealed that AVM vessels express GGTP and GLUT1, markers specific to brain capillaries. Immunofluorescent staining demonstrated that expression of KLF2, a vascular maturation marker is significantly (P <0.001) decreased in AVM vessels and was further confirmed by western blot analysis (P < 0.001). Immunohistochemical and western blot analysis demonstrated that another vascular maturation protein Endoglin had high expression in AVM vessels compared to control vessels. The results were found to be statistically significant (P < 0.0001).SummaryOur findings suggest that vascular structures of AVMs co-express markers specific for arteries, veins and capillaries. We conclude that AVM nidus constitutes of aberrant vessels which are not terminally differentiated and inadequately matured.
Highlights
Arteriovenous malformation (AVM) of the brain is a devastating vascular malformation characterized by direct connections of dilated arteries and veins and a dearth of the normal capillary system
Immunofluorescent staining demonstrated that expression of KLF2, a vascular maturation marker is significantly (P
Histological analysis of AVM nidus revealed that nidus consists of heterogeneous vascular structures with distinct morphological features
Summary
Arteriovenous malformation (AVM) of the brain is a devastating vascular malformation characterized by direct connections of dilated arteries and veins and a dearth of the normal capillary system. Feeding artery, draining vein and nidus are the three parts of the AVM lesion. These lesions can occur in any of the four lobes of the brain and patients with AVM present symptoms such as head ache, seizures, hemorrhage etc. Size of lesion and type of venous drainage, surgical or nonsurgical treatment strategies are selected for AVM cure [1]. Despite much understanding on normal vascular development, mechanisms in the formation of discrete AVM lesions are unclear. Reports on the de-novo formation of AVM have challenged the view on its congenital origin [2]. Vascular malformations could occur when there is a defect in either early or late phase of vascular development
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