Hirata S, Matsubara T, Saura R, Tateishi H, Hirohata K
Department of Orthopedic Surgery, Kobe University School of Medicine, Japan.
Arthritis Rheum. 1989 Sep;32(9):1065-73. doi: 10.1002/anr.1780320903.
Neovascularization in the rheumatoid synovium plays an important role in the propagation of rheumatoid synovitis because the emigration of mononuclear cells and the growth of pannus are critically dependent on the development of small blood vessels. Inhibition of local vascular endothelial cell (EC) proliferation, which is essential for growth of these vessels, therefore, would have the potential to suppress rheumatoid inflammation. We investigated the effects of methotrexate (MTX), low doses of which are commonly administered to rheumatoid arthritis patients, on DNA synthesis by human umbilical vein EC in vitro and on rabbit corneal neovascularization in vivo. MTX inhibited both basal and EC growth factor-stimulated tritiated deoxyuridine (3H-UdR) incorporation into EC in a dose-dependent manner. Significant inhibition was observed at a concentration of 5 x 10(-9) M, which is that attained in the serum of treated patients. Neovascularization in vivo was also suppressed by low-dose intramuscular injections. These results suggest that MTX has an antiangiogenic effect, and may suppress rheumatoid inflammation through the reduction of synovial small blood vessels responsible for mononuclear cell infiltration and proliferation of synovial tissue.
类风湿性滑膜炎中的新生血管形成在类风湿性滑膜炎的进展中起重要作用，因为单核细胞的迁移和血管翳的生长严重依赖于小血管的形成。因此，抑制局部血管内皮细胞（EC）增殖（这是这些血管生长所必需的）可能具有抑制类风湿性炎症的潜力。我们研究了甲氨蝶呤（MTX）（类风湿性关节炎患者常用低剂量给药）对体外人脐静脉内皮细胞DNA合成及体内兔角膜新生血管形成的影响。MTX以剂量依赖的方式抑制基础状态及内皮细胞生长因子刺激的氚标记脱氧尿苷（3H-UdR）掺入内皮细胞。在5×10⁻⁹M浓度时观察到显著抑制，这是治疗患者血清中达到的浓度。低剂量肌肉注射也可抑制体内新生血管形成。这些结果表明MTX具有抗血管生成作用，并可能通过减少负责单核细胞浸润和滑膜组织增殖的滑膜小血管来抑制类风湿性炎症。
