Development Of Cerebral Arteriovenous Malformations Research Articles

Aberrant regulation of retinoic acid signaling genes in cerebral arterio venous malformation nidus and neighboring astrocytes

BackgroundCerebral arterio venous malformations (AVM) are a major causal factor for intracranial hemorrhage, which result in permanent disability or death. The molecular mechanisms of AVM are complex, and their pathogenesis remains an enigma. Current research on cerebral AVM is focused on characterizing the molecular features of AVM nidus to elucidate the aberrant signaling pathways. The initial stimuli that lead to the development of AVM nidus structures between a dilated artery and a vein are however not known.MethodsIn order to understand the molecular basis of development of cerebral AVM, we used in-depth RNA sequencing with the total RNA isolated from cerebral AVM nidus. Immunoblot and qRT-PCR assays were used to study the differential gene expression in AVM nidus, and immunofluorescence staining was used to study the expression pattern of aberrant proteins in AVM nidus and control tissues. Immunohistochemistry was used to study the expression pattern of aberrant proteins in AVM nidus and control tissues.ResultsThe transcriptome study has identified 38 differentially expressed genes in cerebral AVM nidus, of which 35 genes were upregulated and 3 genes were downregulated. A final modular analysis identified an upregulation of ALDH1A2, a key rate-limiting enzyme of retinoic acid signaling pathway. Further analysis revealed that CYR61, a regulator of angiogenesis, and the target gene for retinoic acid signaling is upregulated in AVM nidus. We observed that astrocytes associated with AVM nidus are abnormal with increased expression of GFAP and Vimentin. Triple immunofluorescence staining of the AVM nidus revealed that CYR61 was also overexpressed in the abnormal astrocytes associated with AVM tissue.ConclusionUsing high-throughput RNA sequencing analysis and immunostaining, we report deregulated expression of retinoic acid signaling genes in AVM nidus and its associated astrocytes and speculate that this might trigger the abnormal angiogenesis and the development of cerebral AVM in humans.

Gene Mutations Related to Pathogenesis and Development of Cerebral Arteriovenous Malformations in Pediatric Populations

Abstract INTRODUCTION Cerebral arteriovenous malformations (AVMs) are the most common cause of spontaneous intracranial hemorrhage in pediatric patients. Recurrence after complete surgical resection is a recognized risk that occurs primarily in children. While Pediatric Neurosurgery practices traditionally focus on clinical management, recent advances have found gene mutations to play a role in pathogenesis and development of AVMs It is not known how many pediatric AVMs are sporadic versus arising from familial inheritance patterns. We aimed to see how identified genetic mutations are represented in our AVM patient population in Texas and the southern United States. METHODS We developed a multidiscipinary pediatric neurovascular program at our institution. Patients and families were screened in their first-time and/or follow-up outpatient clinic encounters by our hematologist-oncologist and genetics counsellor from the Pediatric Vascular Anomalies program. Genetic testing recommendations and results were recorded in our IRB-approved ongoing prospective neurovascular database. RESULTS 50 patients were screened in Vascular Anomalies program. Diagnoses ranged from AVMs (n = 20), cerebral cavernous malformations (n = 13), non-NF/non-sickle-cell moyamoya (n = 7), and other lesions such as cerebral proliferative angiopathy and megelencephaly-capillary malformation. Of the 50 patients, 30 underwent genetic testing. 7 had identified mutations. 3 patients with cavernous angiomas had Krit1 mutations. 2 patients with AVMs had Rasa1 mutations, and 2 patients with megenecephaly-capillary malformations had PIK3CA mutations. CONCLUSION These preliminary findings highlight the importance of thinking beyond neurosurgical intervention for pediatric neurovascular diseases. Genetic mutations have been found in 23% of patients screened thus far. Such findings provide insight into disease biology and may likely have clinical implications for risk assessment, family screening, and follow-up surveillance. Further work needs to be done to capture all our AVM population for genetic screening over time, while expanding our neurovascular program's study focus to encompass all neurovascular pathologies.

Expression of angiogenic factors in cerebral arteriovenous malformations

Background In the process of vascularization, vascular endothelial growth factor (VEGF), angiopoietin-2 and Tie2 are involved in the migration, differentiation and proliferation of vascular endothelial cells, and stimulate the rapid angiogenesis; Tie1 and angiopoietin-1 play important roles in facilitating the formation of vascular lumen and maintaining the integrity of vascular wall. Thus the distributions and expressions may be associated with the occurrence of cerebral arteriovenous malformation. Objective To observe the biological effects of angiogenic factors in the occurrence and development of cerebral arteriovenous malformation. Design An observational comparative experiment. Settings Department of Neurosurgery, General Hospital of Shenyang Military Area Command of Chinese PLA; Department of Neurosurgery, General Hospital of Tianjin Medical University. Participants Fresh samples of complete cerebral arteriovenous malformations resected in 47 patients were collected from the Department of Neurosurgery, General Hospital of Tianjin Medical University from August 1999 to May 2001, including 22 males and 25 females, the mean age was 34.5 years. Informed consents were obtained from all the patients or their relatives. The initial symptom was hemorrhage in 28 cases. All the patients were classified according to the clinical imaging data and Spetzler-Martin grading standard, including 11 cases of grade I, 17 cases of grade II, 11 cases of grade III, and 8 cases of grade IV–V. Normal brain tissues resected by decompression due to trauma were taken from 8 patients as controls, including 5 males and 3 females, aging 12–65 years. Methods ▪ The expressions of VEGF, Tie receptors, angiopoietin-1, angiopoietin-2, proto-oncogene c-myc and proliferating cell nuclear antigen(PCNA) in the samples of cerebral arteriovenous malformation were detected with immunohistochemical method. Under light microscope, the positively stained rat-anti-human factor VIII-related antigens (specific marker of vascular endothelial cells) were counted, then the immuno-positive cells of the other antibodies in the visual field of neighboring section which was in “mirror” relation were counted, and the percentage of the latter to the former was considered as the labeling index of positive cells. The immunostaining intensity was classified negative (–): no positive cells; positive (+): number of positive cells < 20%; moderately positive (++): number of positive cells 20%–50%; strongly positive (+++): number of positive cells > 50%. ▪ The differences of the enumeration data were compared with chi-square test, and the correlation were analyzed with the linear correlation analysis. Main outcome measures Expressions and distributions of VEGF, Tie1 and Tie2 receptors, angiopoietin-1, angiopoietin-2, PCNA and c-myc in the samples of cerebral arteriovenous malformation and normal brain tissue. Results ▪ Expressions of angiogenic factors in the control group and cerebral arteriovenous malformation groups of each grade: The positive rates of VEGF, Tie2, angiopoietin-2, c-myc and PCNA expressions in the control group were significantly different from those in the cerebral arteriovenous malformation groups of each grade (χ 2=21.09–34.23, P < 0.05), whereas the positive rates of Tie1 and angiopoietin-1 expressions were close (χ 2=3.43–3.869, P > 0.05). ▪ Expressions of angiogenic factors in hemorrhage group and non-hemorrhage group: The expressions of VEGF, angiopoietin-2 and PCNA in the hemorrhage group were significantly lower than those in the non-hemorrhage group (χ 2=16.22–26.56, P < 0.05). There ware no obvious differences in the expressions of Tie1 and angiopoietin-1 expressions between the hemorrhage group and non-hemorrhage group (χ 2=3.22–3.78, P > 0.05). The VEGF was positively correlated with the expressions of c-myc and PCNA ( r = 0.728, 0.916, P < 0.05). Conclusion ▪ The expressions of angiogenic factors and related receptors may be involved in the process of cerebral arteriovenous malformation, and had important correlation the its clinical grading. ▪ Angiogenic factors may induce the expression of endothelial cell c-myc in cerebral arteriovenous malformation, and then interfere the cell proliferation and apoptosis.

Spontaneous regression of a cerebral arteriovenous malformation in a child with hereditary hemorrhagic telangiectasia

Patients with hereditary hemorrhagic telangiectasia (HHT) are at risk for the development of cerebral arteriovenous malformations (AVMs). The authors report a case of a spontaneously regressing cerebral AVM in a patient with HHT. The lesion was diagnosed on the basis of findings on screening magnetic resonance imaging and regressed completely before any treatment was undertaken. The spontaneous regression of cerebral AVMs is a rare and poorly understood phenomenon. Only one other instance of spontaneous regression of a cerebral AVM in a patient with HHT has been reported in the literature. The authors compare angiographic and clinical features in previously reported cases of spontaneous regression of cerebral AVMs with those in the present case to determine the characteristics common to this phenomenon.

Expression of transforming growth factor-beta complex in arteriovenous malformations.

The factors responsible for the development of cerebral arteriovenous malformations (AVMs) are not well known. Patients with hereditary hemorrhagic telangiectasia (HHT) have cutaneous vascular dysplasia and a high propensity to develop systemic and cerebral AVMs. Transforming growth factor-beta (TGF-beta) complex has been implicated in HHT. The aim of this study was to evaluate the expression of TGF-beta 1, TGF-beta 2, TGF-beta 3, and their two receptors (R1 and R2) in AVMs and in normal brain vessels. Formalin-fixed, paraffin-embedded tissues from 20 patients with cerebral AVMs (including two patients with HHT) were sequentially sectioned into 6 microns sections. Similar sections from normal brain tissue were obtained from five patients without AVMs and no intracranial pathology, who had died from unrelated causes. The normal tissue sections included large intracranial arteries, small arteries, venous sinuses, cortical veins, and brain tissue containing arterioles, capillaries, and venules. All specimens underwent immunohistochemical analyses with polyclonal antibodies to the following antigens: TGF-beta 1, TGF-beta 2, TGF-beta 3, and R1 and R2. The immunoreactivity, when present, was consistently noted in endothelial cells and in the medial smooth muscle. The intensity of vessel wall immunostaining was graded on a scale from 0 to 3. The mean staining grades of normal vessels for TGF-beta 1, TGF-beta 2, TGF-beta 3, R1, and R2 were 0.6 (range 0-1), 3, 2.8 (range 2-3), 1.6 (range 0-2), and 3, respectively, whereas the mean staining grades of AVM vessels were 0.3 (range 0-1), 0.8 (range 0-1), 0.6 (range 0-1), 1.4 (range 0-2), and 0.9 (range 0-1), respectively. The study thus demonstrated that normal brain vessels (arteries, veins, small vessels) have strong (range 2.8-3) immunostaining for TGF-beta 2, TGF-beta 3, and R2, and that the AVM nidus vessels have a paucity (range 0.8-0.9) of staining for these factors. In AVM vessels that had zero immunoreactivity to the above three factors, the vessel wall was fibrocollagenous rather than muscular. Further studies to examine the TGF-beta complex behavior in AVMs are needed.