Regulation of drugs on abnormal neovascularization of choroidal capillaries in diabetic rats

我们研究了脉络膜功能障碍与血管生成在糖尿病视网膜病变发病机制中的作用。(1)建立体外培养系统，研究链脲佐菌素（STZ）致糖尿病大鼠早期和晚期脉络膜毛细血管的状况。以外植体出芽的微血管数量作为体外新生血管的指标。(2)与年龄匹配的正常年轻大鼠相比，糖尿病早期的脉络膜毛细血管在添加和不添加胎牛血清（FBS）的情况下都更容易促进新生血管的形成。(3) N(epsilon)-（羧甲基）赖氨酸（CML）修饰蛋白是晚期糖基化终产物之一，促进脉络膜新生血管的形成。抗CML单克隆抗体6D12抑制糖尿病对脉络膜新生血管的促进作用，但不抑制正常毛细血管新生血管的形成。(4)与对照组相比，早期糖尿病患者培养的脉络膜毛细血管释放出更高浓度的血管内皮和更多的生长因子（VEGF），并有增加肿瘤坏死因子(TNT)- α和血小板衍生生长因子(PDGF)-BB的趋势。(5)粉防己碱，一种主要的双苄基异喹啉生物碱。“Stephania letrandrae s.m moore（根）”及其相关合成化合物（KS-1-4）选择性抑制早期糖尿病患者脉络膜新生血管和VEGF和pdgf - bb促进的脉络膜新生血管。(6)早期糖尿病不影响视网膜毛细血管新生，但新形成的脉络膜毛细血管抑制共培养视网膜新生血管。6D12恢复脉络膜毛细血管诱导的视网膜新生抑制。(7)脉络膜毛细血管促进了正常老年大鼠的新生血管形成，但对晚期糖尿病大鼠没有改变。6D12抑制年龄诱导的脉络膜新生血管。晚期糖尿病患者视网膜毛细血管促进新生血管形成，并通过共培养脉络膜毛细血管增强新生血管形成。综上所述，cml修饰的蛋白在脉络膜毛细血管中积累，释放VEGF，可能是TNF和PDGF。抑制早期糖尿病患者视网膜新生血管的形成。然而，cml修饰的蛋白质通过晚期糖尿病脉络膜毛细血管的血管生成活性来增强视网膜新生血管，从而诱导糖尿病视网膜病变的发病机制。少

We investigated roles of choroidal dysfunction with angiogenesis for induction of pathogenesis in diabetic retinopathy. (1) We developed in vitro culture system to study condition of choroidal capillaries in early and advanced stages of streptozotocin (STZ)-diabetic rats. The mumber of microvessels budded from explants was evaluated as index of in vitro neovascularization. (2) Choroidal capillaries in the early stage of diabetes facilitated neovascularization both with and without fetal bovine serum (FBS) to a greater extent than capillaries in age-matched normal young rats. (3) N(epsilon)-(carboxymthyl)lysine (CML)-modified proteins, one of advanced glycation end products facilitated choroidal neovascularization.6D12, a monoclonal antibody against CML, Suppressed the diabetic stale-facilitation of choroidal neovascularization but not neovascularization in normal capillaries. (4) Cultured choroidal capillaries in early stage-diabetes released higher concentration of vascular endothelia … More l growth factor (VEGF) and tended to increase tumor necrosis factor (TNT)-alpha and platelet-derived growth factor (PDGF)-BB, relative to tle Control. (5) Tetrandrine, a principal bis-benzylisoquinoline alkaloid isolated from."Stephania letrandrae S.Moore (root)" and its related synthetic compound (KS-1-4) selectively inhibited choroidal neovascularization ill early stage-diabetes and VEGF- and PDGF-BB-facilitaled choroidal neovascularization. (6) The early stagediabetes did not affect neovascularization of retinal capillaries but newly formed choroidal capillaries suppressed retinal neovascularization in co-culture. 6D12 restored choroidal capillary-induced suppression of the retinal neovascularization. (7) Choroidal capillaries facililaled neovascularizalion in normal older rat but did not change it in advanced stage-diabetes. 6D12 suppressed age-induced choroidal neovascularization. Retinal capillaries in advanced stage-diabetes facilitated neovascularization and were potentiated neovascularization by co-cultured choroidal capillaries. In conclusion, CML-modified proteins accumulated in choroidal capillary release VEGF, probably TNF and PDGF.and suppress the retinal neovascularization in early stage-diabetes. However, CML-modified proteins potentiated retinal neovascularization through the angiogenic activity of choroidal capillaries in the advanced stage-diabetes to induce pathogenesis of diabetic retinopathy. Less