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

Abstract

Abstract 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.