Afuwape A O, Feldmann M, Paleolog E M
Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, UK.
Gene Ther. 2003 Nov;10(23):1950-60. doi: 10.1038/sj.gt.3302104.
The angiogenic factor VEGF promotes synovitis and bone erosion in rheumatoid arthritis (RA). Previously, we have demonstrated that VEGF expression correlates with disease severity in RA patients and in murine collagen-induced arthritis (CIA). In this study, we adopted an adenoviral gene delivery system expressing soluble VEGF receptor 1 (sFlt-1) to further study the role of VEGF in CIA. Arthritis was induced in DBA/1 mice by injection of bovine collagen. Adenoviruses expressing human soluble VEGF receptor 1 (AdvsFlt-1), or without transgene (Adv0), were injected intravenously on the first day of arthritis. We found that disease severity and paw swelling were significantly suppressed in mice receiving AdvsFlt-1, when compared to untreated or Adv0-treated mice. Expression of sFlt-1 peaked 24 h after injection, with protein detectable in the liver, synovial issue and serum, but rapidly decreased by 72 h. The effect of sFlt-1 expression on signs of disease was paralleled by reduced joint destruction and decreased expression of the vascular marker von Willebrand factor. In summary, adenoviral delivery of human soluble VEGF receptor type 1 significantly suppressed disease activity in CIA. The actions of AdvsFlt-1 are likely to be mediated by reduced synovial neovascularization, and these results support the concept that VEGF blockade may be an effective therapeutic adjunct for the treatment of RA.
血管生成因子血管内皮生长因子（VEGF）可促进类风湿关节炎（RA）中的滑膜炎和骨侵蚀。此前，我们已经证明VEGF表达与RA患者及小鼠胶原诱导性关节炎（CIA）的疾病严重程度相关。在本研究中，我们采用表达可溶性VEGF受体1（sFlt-1）的腺病毒基因递送系统，进一步研究VEGF在CIA中的作用。通过注射牛胶原蛋白在DBA/1小鼠中诱导关节炎。在关节炎发作的第一天静脉注射表达人可溶性VEGF受体1的腺病毒（AdvsFlt-1）或无转基因的腺病毒（Adv0）。我们发现，与未治疗或Adv0治疗的小鼠相比，接受AdvsFlt-1的小鼠疾病严重程度和爪肿胀明显受到抑制。sFlt-1的表达在注射后24小时达到峰值，在肝脏、滑膜组织和血清中可检测到蛋白质，但在72小时时迅速下降。sFlt-1表达对疾病体征的影响与关节破坏减少和血管标志物血管性血友病因子表达降低平行。总之，腺病毒递送人可溶性VEGF受体1可显著抑制CIA中的疾病活动。AdvsFlt-1的作用可能是通过减少滑膜新生血管形成介导的，这些结果支持VEGF阻断可能是治疗RA的有效辅助治疗方法这一概念。
