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
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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
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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 (χ2=21.09–34.23, P < 0.05), whereas the positive rates of Tie1 and angiopoietin-1 expressions were close (χ2=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 (χ2=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 (χ2=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
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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.
