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Hypoxia-inducible Factor and Vascular Endothelial Growth Factor Are Expressed More Frequently in Embolized than in Nonembolized Cerebral Arteriovenous Malformations

Sure, Ulrich M.D.; Battenberg, Elmar M.S.; Dempfle, Astrid M.Sc.; Tirakotai, Wuttipong M.D.; Bien, Siegfried M.D.; Bertalanffy, Helmut M.D.

doi: 10.1227/01.NEU.0000134556.20116.30
Clinicopathological Study

OBJECTIVE: In previous studies, we documented a marked neoangiogenesis and endothelial proliferation in cerebral arteriovenous malformations (AVMs) that were embolized before surgery compared with those that were not embolized. We hypothesized that embolization caused a local hypoxia that promotes neoangiogenesis as a possible pathomechanism. To support this hypothesis, we now examined the angiogenesis-related proteins in a larger cohort of patients. In addition, we investigated hypoxia-inducible factor-1α as a possible protein operative during neoangiogenesis of cerebral AVMs.

METHODS: Paraffin-embedded specimens of 56 AVMs obtained from surgical resection and 14 brain tissue controls were immunohistochemically stained with antibodies to proliferating cell nuclear antigen, MIB-1, vascular endothelial growth factor, Flk1, and hypoxia-inducible factor-1α by standard protocols.

RESULTS: In AVMs treated with embolization before surgery (n = 35, 63%), the expression of hypoxia-inducible factor-1α (P = 0.0101) and vascular endothelial growth factor (P = 0.0007) was significantly higher (Fisher’s exact test) than in patients who did not have previous endovascular treatment. Differences in the expression of Flk-1 (P = 0.0798) and proliferating cell nuclear antigen (P = 0.0423) were in the same direction but were not significant when corrected for multiple testing.

CONCLUSION: Our results provide circumstantial evidence that a partial occlusion of cerebral AVMs might induce local hypoxia-related neoangiogenesis. To support these data, future animal studies should be performed.

Author Information

Neurochirurgische Klinik, Philipps-University, Marburg, Germany

Neurochirurgische Klinik, Philipps-University, Marburg, Germany

Institut für Medizinische Biometrie und Epidemiologie, Philipps-University, Marburg, Germany

Neurochirurgische Klinik, Philipps-University, Marburg, Germany

Abteilung für Neuroradiologie, Philipps-University, Marburg, Germany

Neurochirurgische Klinik, Philipps-University, Marburg, Germany

Reprint requests: Ulrich Sure, M.D., Department of Neurosurgery, Philipps-University, Baldingerstraße, 35033 Marburg, Germany. Email:

Received, May 22, 2003

Accepted, October 7, 2003

Copyright © by the Congress of Neurological Surgeons