促红细胞生成素对缺血性视网膜病变分子作用机制的研究进展

促红细胞生成素（EPO）是一种内源性细胞因子,具有调节红细胞生成等多种生物学效应。既往研究证实,EPO是一种独立的促新生血管形成因子,与缺血缺氧导致视网膜新生血管的发生密切相关,尤其是在早产儿视网膜病变（ROP）中起重要作用。近年来EPO与糖尿病视网膜病变（DR）关系的实验研究发现,在糖尿病早期EPO作为神经营养因子主要起保护作用,然而一旦进入增生期,EPO具有与血管内皮生长因子（VEGF）相似的促进血管生成的潜力。此外,最新临床研究证实玻璃体腔注射EPO对目前治疗无效的顽固性糖尿病黄斑水肿（DME）患者有一定的疗效。就EPO及其受体在缺血性视网膜病变中的分子作用及机制的研究进展进行综述。     

光动力方法静脉阻塞诱导小鼠实验性视网膜新生血管

视网膜新生血管（RNV）见于多种眼部疾病，如糖尿病视网膜病变、视网膜静脉阻塞（RVO）及早产儿视网膜病变等，是导致严重的视力障碍及最终失明的重要原因。建立合适的RNV动物模型对了解RNV发病机制和开发新疗法具有重要意义。我们采用光动力方法建立小鼠实验性RVO模型，诱导视网膜缺血和RNV，为RNV研究提供更理想的动物模型。     

生长因子诱导的血管内皮细胞增殖作用的研究

目的 研究生长因子对血管内皮细胞增殖活动的诱导和刺激作用。以进一步探讨生长因子在视网新生血管疾病中所起的作用。方法 采用血管内皮生长因子（VEGF）和碱性成纤维生长因子（bFGF）诱导离体培养的血管内皮细胞的增殖。研究VEGF及bFGF对血管内皮细胞DNA合成、细胞生长和细胞周期的调控，以及两种因子的协同效应。结果 VEGF及bFGF均可显著刺激血管内皮细胞的增生，其刺激效应与生长因子浓度呈剂量依赖关系。共同作用时，具有协同效应。两种因子均可显著增加^3H-TdR的掺入量，其刺激作用与浓度呈剂量依赖关系，共同作用时亦具有协同效应。VEGF和bFGF均可显著地产加S期细胞的比例。结论 VEGF及bFGF均可显著地刺激内皮细胞的增殖，促进细胞DNA的合成。两种因子联合应用时，具协同效应。提示：两种生长因子在视网膜新生血管的发生和发展中可能具有一定作用，且存在因子间的协同效应。     

bFGF对兔视网膜Müller细胞表达VEGF的影响

血管内皮生长因子（VEGF）和碱性成纤维细胞生长因子（bFGF）是视网膜细胞分泌的两种最重要的血管生成因子。二者有协同作用，bFGF还可以诱导内皮细胞表达VEGF。视网膜Müller细胞是视网膜中分泌VEGF的主要细胞之一，为了进一步探讨Müller细胞在糖尿病视网膜病变（DR）中的作用，本研究观察了bFGF对体外培养免视网膜Müller细胞表达VEGF的影响。     

诱导型一氧化氮合成酶与视网膜新生血管形成的关系

新生血管生成是缺氧诱导的各种视网膜病变的主要病理变化之一.诱导型一氧化氮合成酶(inducible nitric oxide synthase,iNOS)在此过程中起重要作用,其作用机制错综复杂,且与多种促血管生成因子密切相关.为了阐明iNOS的作用机制,iNOS抑制剂的研究也逐渐受到重视,而使用选择性iNOS抑制剂来抑制视网膜新生血管(Retinal neovascularization,RNV)已成为该领域一大研究热点.本文就iNOS及其抑制剂在RNV形成过程中的作用机制及研究进展进行简要综述.     

糖尿病视网膜病变缺血再灌注损伤中相关调控因子的研究进展

糖尿病视网膜病变（DR）是一种常见的缺血性眼病。DR视网膜缺血再灌注（RIR）损伤的缺血过程、再灌注损伤过程及其结局3个阶段中氧化应激、钙超载、一氧化氮（NO）、兴奋性氨基酸（EAA）等因素引起多种炎性介质和基因过度表达,进而造成炎症反应、损伤、凋亡和坏死等组织改变和功能障碍。这些过程受凋亡基因、促红细胞生成素、单核细胞趋化蛋白1、血管内皮生长因子（VEGF）、碱性成纤维细胞生长因子（bFGF）、基质细胞衍生因子-1、NO、一氧化氮合酶（NOS）等多种相关因子的调控。就其中主要调控因子的特点及临床应用方面的研究进展进行综述。     

加强视网膜新生血管发生发展机制研究,为预防和治疗视网膜新生血管性疾病奠定基础

视网膜新生血管(RNV)形成是促血管生成因子和血管生成抑制因子之间平衡失调的一个复杂病理生理过程.正确理解RNV发生的相关信号通路及调控机制,深入探索启动RNV发生发展的关键因素,从重塑新生血管发生的角度出发,寻求改善RNV性疾病的新靶点均有助于深入了解RNV的发生发展机制,为临床预防和治疗RNV性疾病带来新的希望.     

肝细胞生长因子与视网膜新生血管形成

视网膜新生血管形成可造成眼部多种组织成分的广泛损害,已成为世界范围的致盲性疾病.其发生及发展过程复杂,需要多种因素参与,包括多种生长因子的相互作用等.肝细胞生长因子（HGF）作为多效性生长因子,对新生血管形成的作用逐渐被认识.本文主要探讨HGF在视网膜新生血管发病机制中的作用以及与血管内皮生长因子（VEGF）的关系.     

加强视网膜新生血管发生发展机制研究,为预防和治疗视网膜新生血管性疾病奠定基础

视网膜新生血管(RNV)形成是促血管生成因子和血管生成抑制因子之间平衡失调的一个复杂病理生理过程.正确理解RNV发生的相关信号通路及调控机制,深入探索启动RNV发生发展的关键因素,从重塑新生血管发生的角度出发,寻求改善RNV性疾病的新靶点均有助于深入了解RNV的发生发展机制,为临床预防和治疗RNV性疾病带来新的希望.     

细胞因子与糖尿病视网膜病变的研究进展

糖尿病视网膜病变（DR）是一种发生进行性视力损害的糖尿病（DM）并发症,其特征是毛细血管闭锁、微循环障碍和局部缺血性视网膜新生血管形成,其确切的发病机制尚不清楚。最近有研究认为DR可能与视网膜毛细血管炎症反应有关。由于细胞因子能引起炎症反应和黏附分子表达,因此细胞因子增加单核细胞和内皮细胞黏附的过程被认为是DR发生发展过程中的关键事件。就血管内皮生长因子（VEGF）、转化生长因子-β（TGF-β）、碱性成纤维细胞生长因子（bFGF）等多种细胞因子在DR中的作用进行综述。     

色素上皮衍生因子及其治疗视网膜新生血管性疾病的研究进展

视网膜新生血管（RNV）是目前最主要的致盲病因之一,迄今为止,尚无特效治愈方法。色素上皮衍生因子（PEDF）是新近发现的一种有效的眼内新生血管天然抑制剂,对新生血管的形成和发展起着重要的调控作用。有研究结果表明,应用PEDF重组蛋白或PEDF的眼内基因转移可以显著抑制RNV的形成,这为糖尿病性视网膜病变、早产儿视网膜病变及视网膜中央静脉阻塞等视网膜新生血管性疾病的治疗开辟了崭新的途径。因此,有必要就PEDF的生物学概况、对新生血管抑制作用的特点和机制及其在视网膜新生血管防治中的应用前景进行综述。（中华眼科杂志,2007,43：1043．1047）     

APELIN/APJ系统:抗眼内新生血管的新靶点

视网膜新生血管形成是增生性糖尿病视网膜病变、早产儿视网膜病变及缺血性视网膜中央静脉阻塞等视网膜疾病的共同并发症,是这些疾病致盲的主要原因.研究表明多种因子参与新生血管的形成,如血管内皮生长因子、碱性成纤维细胞生长因子等.APELIN是孤儿G蛋白藕连受体(orphan G-protein-coupled receptor,GPCR) APJ的内源性配体,广泛分布于各种组织,具有多种生物学功能.新近研究表明,APELIN在生理及病理性血管新生中具有重要作用,可能成为抗眼内新生血管的新靶点.     

Inhibition of pathological retinal angiogenesis by the integrin αvβ3 antagonist tetraiodothyroacetic acid (tetrac)

Retinal angiogenesis is a major cause of blindness in ischemic retinopathies including diabetic retinopathy and retinopathy of prematurity. Integrin αvβ3 is a promising therapeutic target for ocular angiogenesis, modulating the pro-angiogenic actions of multiple growth factors. In this study, we sought to determine the effects of the integrin αvβ3 antagonist tetra-iodothyroacetic acid (tetrac) on the angiogenic actions of VEGF and erythropoietin (EPO) in cultured human retinal endothelial cells. In addition, we investigated the effect of tetrac and a nanoparticulate formulation of tetrac on retinal angiogenesis in?vivo, in the mouse oxygen-induced retinopathy (OIR) model. Tetrac inhibitory activity was evaluated in human retinal endothelial cells treated with VEGF and/or EPO. Endothelial cell proliferation, migration, and tube formation were assessed, in addition to phosphorylation of ERK1/2. For the studies of the oxygen-induced retinopathy model, C57BL/6 mice were exposed to 75% oxygen from postnatal day (P)7 to P12, and then returned to room air. Tetrac and tetrac-nanoparticle (tetrac-NP) were administered at P12 and P15 by either intraperitoneal or intravitreal injection. Retinal neovascularization was quantitated at P18. Tetrac significantly inhibited pro-angiogenic effects of VEGF and/or EPO on retinal endothelial cells, indicating that the angiogenic effects of both growth factors are dependent on integrin αvβ3. Retinal neovascularization in the OIR model was significantly inhibited by both tetrac and tetrac-NP. These results indicate that the integrin αvβ3 antagonist, tetrac, is an effective inhibitor of retinal angiogenesis. The ability of tetrac to inhibit the pro-angiogenic effect of both VEGF and EPO on retinal endothelial cells suggests that tetrac (and antagonism of integrin αvβ3) is a viable therapeutic strategy for proliferative diabetic retinopathy.     

Angiopoietin‐like protein 4 (ANGPTL4) is induced by high glucose in retinal pigment epithelial cells and exhibits potent angiogenic activity on retinal endothelial cells

Purpose: Hyperglycaemia has been identified as major risk factor for diabetic retinopathy (DR). It is widely accepted that the progression of DR is mainly due to a local imbalance of pro‐ versus anti‐angiogenic factors in the retina. In this study, we investigated whether retinal pigment epithelial (RPE) cells produced pro‐angiogenic factors under high glucose (HG) conditions in vitro. Methods: Cultured human retinal endothelial (RE) cells were exposed to conditioned medium from retinal pigment epithelium cells (ARPE‐19) grown in HG medium and assessed for tube formation. Based on the expression profiles of ARPE‐19, we investigated whether ANGPTL4 was a major angiogenic factor released from ARPE‐19 under HG conditions using cultured human RE cells as the test system for experiments with recombinant protein, conditioned medium from ARPE‐19 and RNA interference (RNAi). Results: The conditioned medium from ARPE‐19 cultured under HG conditions promoted tube formation of cultured human RE cells. GeneChip analysis showed that ANGPTL4 was one of the highest upregulated genes under HG conditions. In addition, recombinant ANGPTL4 promoted all of the elements of angiogenesis in human RE cells in vitro. The results of experiments using conditioned medium from ARPE‐19 combined with RNAi demonstrated that ANGPTL4 was a major angiogenic factor released from ARPE‐19 under HG conditions. Conclusions: ANGPTL4 was induced by high glucose in RPE cells and exhibited potent angiogenic activity on RE cells. Our results are unique and may potentially add a new candidate to the long list of molecules involved in diabetic retinopathy.     

Angiogenic factors in human proliferative sickle cell retinopathy

BACKGROUND/AIMS: Preretinal neovascular formations called sea fans develop at the border of non-perfused peripheral retina in sickle cell retinopathy. Angiogenic factors which could contribute to their development, however, have not been examined previously. The objective of this study was to determine immunohistochemically if vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) were associated with sea fan formations. METHODS: Immunohistochemistry on cryosections was used to localise bFGF, VEGF, heparan sulphate proteoglycan, human serum albumin, collagens IV and II, and von Willebrand factor in tissue from five sickle cell and one control subject. RESULTS: The greatest immunoreactivity for VEGF and bFGF was in the feeder and preretinal vessels of sea fans (p<0.01). The most prominent reaction product was localised to vascular endothelial cells. In retinal vessels, VEGF and bFGF immunoreactivities were greater in sickle cell subjects (both proliferative and non-proliferative) than in the control subject (p<0.01 and p<0.02 respectively). In the sickle cell retina, no angiogenic factor immunoreactivity was detected in non-perfused periphery and there was no significant difference in bFGF or VEGF immunoreactivity between perfused retina and the border of perfused and non-perfused areas. CONCLUSION: Our results demonstrate for the first time that VEGF and bFGF are associated with sea fan formations in sickle cell retinopathy. Both factors may function in an autocrine manner because immunoreactivity for these factors was greater within the neovascularisation than in adjacent retina.     

Roundabout4在肿瘤血管新生及细胞迁移中作用的研究进展

视网膜新生血管性疾病是世界范围内最严重的致盲性眼病之一,包括糖尿病视网膜病变、年龄相关性黄斑变性等。近年来普遍认为血管生长因子是调控视网膜内皮细胞增生和新生血管形成的最主要因素。Roundabout 4（Rob04）是近年发现的一种跨膜蛋白,特异性表达于血管生成活跃的内皮细胞表面。目前的研究认为,Rob04能够调控内皮细胞的迁移及血管新生,参与血管生长因子的信号转导途径,在血管稳定性的调节中发挥重要作用。对Rob04的深入研究将有助于揭示视网膜新生血管性疾病的形成机制。就Rob04的分布、结构、配体及在血管发生、内皮细胞迁移中的作用及与眼部相关的基础研究进行综述。     

早产儿视网膜病变大鼠模型中bFGF的表达

目的：研究bFGF在早产儿视网膜病变（ROP）大鼠模型中的表达水平,以探讨ROP可能的发病机制。方法：以SD大鼠为模型动物,用高氧诱导建立模型,采用免疫组织化学SABC法检测bFGF蛋白水平,逆转录聚合酶链式反应（RT-PCR）法检测bFGFmRNA水平。结果：SABC法显示正常组中bFGF蛋白微弱阳性染色,而高氧组阳性染色明显增强,前者灰度平均值明显高于后者,差异有统计学意义（P〈0.05）;RT-PCR法显示高氧组bFGFmRNA与GAPDHmRNA的比值显著高于正常组,其差别亦有统计学意义（P〈0.05）。结论：bFGF参与了视网膜新生血管（RNV）的形成,与ROP的发病机制有关。     

Regulation of connective tissue growth factor gene expression in retinal vascular endothelial cells by angiogenic growth factors

Background: Connective tissue growth factor (CTGF) is a novel, cysteine-rich secreted protein, which is implicated in fibrotic disorders and atherosclerosis. To elucidate the role of CTGF in fibrovascular proliferative retinopathy, we investigated the regulation of CTGF gene expression in a cell line of retinal vascular endothelial cells (RVEC) stimulated with fetal calf serum (FCS) and angiogenic growth factors, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor-BB (PDGF-BB), endothelial growth factor (EGF), transforming growth factor-β1 and -β3 (TGF-β1, TGF-β3), and insulin-like growth factor-I (IGF-I). Methods: RVEC derived from Macaca mulatta (CRL-1780; ATCC) were stimulated with 10% FCS as well as with VEGF, bFGF, PDGF-BB, TGF-β1, TGF-β3, EGF, or IGF-I. Time-dependent CTGF gene expression was assessed by northern blot analysis. Results: FCS, TGF-β1, TGF-β3, bFGF, and EGF induced an upregulation of CTGF gene expression in RVEC in a time-dependent manner. Highest expression was induced with TGF-β1. No response on CTGF gene ex- pression could be detected to VEGF, PDGF-BB, or IGF-I. Conclusion: The present study demonstrates for the first time that CTGF mRNA is expressed at high levels in RVEC, and that the level of the temporal pattern of its expression is differentially regulated by angiogenic growth factors, indicating a significant role of CTGF in the pathological course of uncontrolled retinal angiogenesis. Received: 3 November 1998 Revised: 23 May 2000 Accepted: 26 June 2000     

Understanding ischemic retinopathies: emerging concepts from oxygen-induced retinopathy

Ischemic retinopathies, such as retinopathy of prematurity and diabetic retinopathy are characterized by an initial microvascular degeneration, followed by an abnormal hypoxia-induced neovascularization. Oxygen-induced retinopathy (OIR) is a well-established in vivo model of ischemic retinopathies, which, although the triggering insult varies, all share a common end result of capillary loss. Understanding the mechanisms of normal retinal vascular development as well as the pathophysiological processes leading to the primary vascular loss is the key to develop treatments to prevent the sight-threatening neovascularization associated with human ischemic retinopathies. The importance of oxygen-dependant vascular endothelial growth factor in the pathophysiology of both phases of OIR has long been recognized. However, recent studies point out that OIR is a multifactorial disease, resulting from additive effects of an unbalanced expression of pro- and anti-angiogenic factors, interrelated with protective effects of nutritional factors and cytotoxic effects of oxidative and nitro-oxidative stress-dependant mediators. This review summarizes the most recent aspects of the research on OIR conducted in our laboratory and others, with a particular focus on the role of new mediators of nitro-oxidative stress, the trans-arachidonic acids, in microvascular degeneration, and on a novel pathway of metabolic signaling where hypoxia-driven succinate, via receptor GPR91, governs normal and pathological retinal angiogenesis.