硬膜動静脈瘻モデルにおける血管内皮増殖因子の発現

Vascular Endothelial Growth Factor Expression in the Rat Dural Arteriovenous Fistula Model

　要旨　目的：硬膜動静脈瘻（DAVF）の成因および病態を検討するために，ラットDAVFモデルを用いて慢性脳静脈圧亢進状態からDAVFが発生する際の血管内皮増殖因子 （VEGF）の発現を検討した。

　方法：雄ウィスターラット6～8週齢（n＝40）を用いた。DAVF モデルは，Spetzler group^{14, 18）}の方法を改良した。ラットは1週間後に硬膜を含めて脳を摘出し，VEGFの発現を免疫染色により観察した免疫染色群（n＝15）と，90日後の血管撮影群（n＝15）の2群に分け，それぞれsham群（n＝5）と比較した。

　結果：Sham群では血管撮影上の変化やVEGFの発現は明らかでなかった。免疫染色群では，硬膜の静脈洞近傍の血管内皮と結合組織に15匹中5匹（33％）で，脳の皮質，基底核の神経細胞に，15匹中11匹（73％）にVEGFの発現がみられた。血管撮影群で15匹中6匹（40％）で主に内頸動脈の髄膜枝からの動静脈シャントがみられた。

　結語：脳静脈圧亢進状態により虚血に陥った組織近傍に血管新生因子が発現し，DAVFが発生することが示唆された。

Although various mechanisms of the development of dural arteriovenous fistula （DAVF） have been proposed, the pathogenesis of these lesions are still unclear. Recent experimental evidence suggested a role of angiogenic growth factors in the genesis of vascular malformations of the central nervous system. To further investigate the pathogenesis of DAVF, we examined the expression of the angiogenic growth factor, vascular endothelial growth factor （VEGF）, in rat DAVF model.

Material and Methods : Male Wistar rats （weighting 280 to 300g, n＝40） were used. Each rat was mounted on a stereotaxic frame under general anesthesia. DAVF model （Spetzler et al.） was made by common carotid artery-external jugular vein anastomosis, bipolar coagulation of the vein draining the transverse sinus, and superior sagittal sinus thrombosis （SSS）. SSS was thrombosed by a hemostatic agent through 16-gauge needle. Venous hypertension was induced in 30 rats, which were divided into two experimental groups; （1） immunohistological study group （n＝15） and （2） angiography group （n＝15）. Immunohistological analysis was performed by VEGF antibody 1 week after, and angiography was done 90 days after the surgery. Developing of angiographical DAVF was observed with the magnifying X-ray camera. Each 5 rats served as sham-operated controls, which received a similar surgery without induction of venous hypertension.

Results : VEGF expression and DAVF were not observed in sham group. In immunohistological study group, VEGF expression in the endothelium and the connective tissues of the dura mater in the five rats （33％） and in the neurons in the eleven rats （73％） of the cerebral cortex and the basal ganglia were identified. In angiography group, DAVF formed in 6 among 15 rats （40％）.

Conclusion : The findings of this study provide the first experimental evidence that angiogenic growth factors VEGF may participate in the genesis of DAVF. These results suggest a novel strategy for the management and prevention of DAVF and related disorders.