Expression of vascular endothelial growth factors and their receptors in and around intracranial arteriovenous malformations

OBJECTIVE: The precise mechanisms responsible for the development and growth of intracranial arteriovenous malformations (AVMs) remain unclear, but it has been hypothesized that vascular endothelial growth factors (VEGFs) might be involved in their pathogenesis. The aim of this study was to examine immunohistochemically the presence of the VEGF family (VEGF-A to -D) and their receptors (Flt-1, Flk-1, and Flt-4) in the surgically resected AVM nidus. METHODS: The AVM nidus was surgically obtained from 31 patients with AVMs (mean age, 40.5 yr, range 13-73 yr). The mean size of the nidus was 31.6 mm (range, 15-60 mm). Formalin-fixed, paraffin-embedded specimens were stained immunohistochemically by the labeled streptavidin-biotin method with antibodies against VEGF-A to -D, as well as Flt-1, Flk-1, and Flt-4. RESULTS: Positive staining for VEGF-A to -D was observed in the endothelial cells of the abnormal vessels involved in the AVM nidus and in the cytoplasm of astroglia surrounding it. Samples from 30 (96.8%) of 31 patients stained positive for VEGF-A, 4 (9.7%) for VEGF-B, 17 (54.5%) for VEGF-C, and 16 (51.6%) for VEGF-D. Flt-1, Flk-1, and Flt-4 were also positive chiefly, but not exclusively, in the cytoplasm of vascular endothelium and smooth muscle cells of the vascular wall. With regard to VEGF receptors, it was found that among the 31 patients studied, 19 (61.3%) were immunohistochemically positive for Flt-1, 6 (19.4%) for Flk-1, and 19 (61.3%) for Flt-4. A comparison of mean nidus size and average age at operation revealed significant differences between patients positive for VEGF-C, VEGF-D, Flt-1, or Flt-4. In contrast, there were no significant differences in nidus size and age in patients positive for VEGF-A, VEGF-B, and Flk-1. CONCLUSION: These results strongly suggest a possible contribution of the VEGF-VEGF receptor system to the growth of intracranial AVMs.