Vinores S A, Chan C C, Vinores M A, Matteson D M, Chen Y S, Klein D A, Shi A, Ozaki H, Campochiaro P A
The Wilmer Ophthalmologic Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287-9289, USA.
J Neuroimmunol. 1998 Aug 14;89(1-2):43-50. doi: 10.1016/s0165-5728(98)00075-7.
Experimental autoimmune uveoretinitis (EAU) was induced in Lewis rats and B10.A mice by immunization with S-antigen (S-Ag) to study the potential roles of vascular endothelial growth factor (VEGF) and the beta1 and beta2 isoforms of transforming growth factor (TGFbeta1 and TGFbeta2) during the progression of the disease. VEGF has been implicated as an angiogenic factor in ischemic retinopathies; however, Lewis rats developing EAU have high levels of VEGF in the retina, but no neovascularization. In the present study, immunohistochemical staining for VEGF, TGFbeta1 and TGFbeta2 was performed on the retinas of Lewis rats developing EAU or with oxygen-induced ischemic retinopathy. In rats immunized with S-antigen, a marked upregulation of VEGF was immunohistochemically visualized from the inner nuclear layer to the inner limiting membrane prior to blood-retinal barrier (BRB) failure and lymphocytic infiltration. VEGF is normally induced by hypoxia and its induction leads to neovascularization. Coincident with the increase in VEGF, there was increased immunoreactivity for TGFbeta1 and TGFbeta2 within the same layers of the retina. In contrast, rats with ischemic retinopathy and retinal neovascularization showed only a modest increase in VEGF immunoreactivity, which is largely confined to retinal ganglion cells and inner retinal vessels, and little or no increase in TGFbeta1 or TGFbeta2. In addition, in mice developing EAU, which does not have an abrupt onset as it does in rats and may involve neovascularization, a comparable upregulation of VEGF in the inner retina to that seen in rats developing EAU occurs with no increase in TGFbeta1 or TGFbeta2. Since TGFbeta can inhibit endothelial cell proliferation, it is likely that an increase in TGFbeta may prevent VEGF from exerting its endothelial growth activity in the rat EAU model, but VEGF may be operative in inducing BRB failure. These data suggest that there is a complex interaction among growth factors in the retina and that retinal neovascularization may require an imbalance between stimulatory and inhibitory factors.
通过用S抗原（S-Ag）免疫Lewis大鼠和B10.A小鼠诱导实验性自身免疫性葡萄膜视网膜炎（EAU），以研究血管内皮生长因子（VEGF）以及转化生长因子β1和β2亚型（TGFβ1和TGFβ2）在疾病进展过程中的潜在作用。VEGF被认为是缺血性视网膜病变中的一种血管生成因子；然而，发生EAU的Lewis大鼠视网膜中VEGF水平很高，但没有新生血管形成。在本研究中，对发生EAU或氧诱导的缺血性视网膜病变的Lewis大鼠视网膜进行了VEGF、TGFβ1和TGFβ2的免疫组织化学染色。在用S抗原免疫的大鼠中，在血视网膜屏障（BRB）破坏和淋巴细胞浸润之前，从内核层到内界膜免疫组织化学观察到VEGF明显上调。VEGF通常由缺氧诱导，其诱导会导致新生血管形成。与VEGF增加同时，视网膜同一层内TGFβ1和TGFβ2的免疫反应性也增加。相比之下，患有缺血性视网膜病变和视网膜新生血管形成的大鼠VEGF免疫反应性仅适度增加，主要局限于视网膜神经节细胞和视网膜内血管，TGFβ1或TGFβ2几乎没有增加或没有增加。此外，在发生EAU的小鼠中，其不像大鼠那样突然发病且可能涉及新生血管形成，视网膜内层VEGF的上调与发生EAU的大鼠相当，但TGFβ1或TGFβ2没有增加。由于TGFβ可以抑制内皮细胞增殖，TGFβ增加很可能在大鼠EAU模型中阻止VEGF发挥其内皮生长活性，但VEGF可能在诱导BRB破坏中起作用。这些数据表明视网膜中生长因子之间存在复杂的相互作用，并且视网膜新生血管形成可能需要刺激因子和抑制因子之间的失衡。
