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.


CONCLUSIONS
These results strongly suggest a possible contribution of the VEGF-VEGF receptor system to the growth of intracranial AVMs.
Koizumi
Toru
T
Department of Neurosurgery, Saga Medical School, 5-1-1 Nabeshima, Saga City, Saga 849-8501, Japan. koizumi@post.saga-med.ac.jp
Shiraishi
Tetsuya
T
Hagihara
Naoshi
N
Tabuchi
Kazuo
K
Hayashi
Takashi
T
Kawano
Teruaki
T
D000293:Adolescent; D000328:Adult; D000368:Aged; D002536:Cerebral Arteries / Q000473:pathology; D016228:Endothelial Growth Factors / Q000032:analysis*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D002538:Intracranial Arteriovenous Malformations / Q000473:pathology* / Q000601:surgery; D008222:Lymphokines / Q000032:analysis*; D008297:Male; D008875:Middle Aged; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis*; D017978:Receptors, Growth Factor / Q000032:analysis*; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor