视网膜与新生血管抑制因子

抑制新生血管生长是视网膜新生血管性疾病的治疗关键。促生长因子和抑制因子共同调控血管的形成，二的平衡控制新生血管的生成。新生血管抑制因子的治疗已成为有前景的新生血管治疗方法。本就与视网膜新生血管研究有关的新生血管抑制因子研究进展进行综述。     

内皮抑素抑制糖尿病视网膜新生血管生成中的研究进展

糖尿病视网膜病变(DR)是眼科常见病,常导致患者视力不可逆性下降,其2大特征包括黄斑水肿,视网膜新生血管生成;而视网膜新生血管生成是导致患者视力丧失最重要的原因之一.内皮抑素(ES)各种作用的发挥与其特有的结构特点密不可分,是目前公认的最强的抑制血管生长的因子之一,ES抑制视网膜新生血管的作用机制复杂,且尚未完全明确.因此,本文拟从ES调控细胞外基质的表达、抑制促血管生成蛋白的表达、调控关键信号通路的表达3个方面阐述ES抑制糖尿病视网膜新生血管病变的可能机制,并作一综述.     

视网膜新生血管的治疗研究进展

视网膜新生血管的发生是众多促血管生成因子间协同作用的结果.病理状态下以基质金属蛋白酶、促红细胞生成素、整合素为代表的促血管生成因子,可通过不同的作用途径,促进视网膜新生血管的发生.有研究者将促视网膜新生血管形成因子作为"靶点"进行靶向治疗研究,可有效地抑制视网膜新生血管的发生.为进一步了解其靶向治疗的机制和效果,有必要就视网膜新生血管形成中的靶分子和靶向治疗研究进展予以阐述,以期为视网膜新生血管的临床治疗提供理论依据.     

血管能抑素抑制新生血管生成的研究进展

血管能抑素是最新发现的一种内源性血管抑制因子,来源于Ⅳ型胶原.实验证明其在体外能显著抑制血管内皮细胞的增生和迁移,诱导其凋亡,在体内能抑制肿瘤新生血管生成.血管能抑素作为抗血管生成治疗的新策略,在眼科基因治疗方面有很好的应用前景,尤其是视网膜新生血管.本文就血管能抑素的发现、命名、生物学特性、作用机制及在眼科应用前景作一综述.     

视网膜与新生血管抑制因子

抑制新生血管生长是视网膜新生血管性疾病的治疗关键。促生长因子和抑制因子共同调控血管的形成 ,二者的平衡控制新生血管的生成。新生血管抑制因子的治疗已成为有前景的新生血管治疗方法。本文就与视网膜新生血管研究有关的新生血管抑制因子研究进展进行综述。     

促红细胞生成素在眼部新生血管疾病发病中的作用

眼部新生血管是一组难治性致盲性眼病的共同临床表现.多种促新生血管因子是其发病的主要机制.促红细胞生成素(erythropoietin,EPO)不仅具有调节红细胞生成的作用,也是一种促新生血管因子,在生理和病理性血管形成过程中起重要作用.EPO在角膜新生血管、视网膜新生血管等形成过程中表达增加,在氧诱导的视网膜新生血管动物模型中,阻断EPO信号可以抑制新生血管形成.这些研究提示EPO在眼部新生血管疾病中起重要作用,有望成为治疗眼部新生血管的新靶点.     

视网膜新生血管性疾病与血管生长促进因子

视网膜新生血管性疾病是世界范围最严重致盲性眼病之一，其发病机制尚未明了，但近年来生长因子在视网膜新生血管形成中的作用已形成共识。本文就与视网膜新生血管相关的血管生长促进因子作一综述。     

色素上皮衍生因子在糖尿病视网膜病变中的研究进展

色素上皮衍生因子(Pigment epithelium-derived factor,PEDF)是与糖尿病视网膜病变关系密切的因子之一.PEDF通过抑制视网膜内皮细胞生长和迁移,弱化血管新生而延缓糖尿病视网膜病变病程进展和减轻视网膜的损伤.PEDF成为未来治疗糖尿病视网膜病变的新药具有广阔前景.本文就PEDF的功能及其在治疗糖尿病视网膜病变中的新进展进行综述.     

糖尿病视网膜病变发病机制中VEGF与PEDF的研究进展

糖尿病视网膜病变(diabeic retinopathy,DR)是糖尿病最常见和最严重微血管并发症之一,其基本病理改变是血-视网膜屏障(blood retinal barrier,BRB)破坏,新生血管形成.后期新生血管膜收缩牵拉视网膜脱离.DR的发病机制十分复杂,至今尚未完全阐明.任何病理改变在本质上均是体内动态平衡的失调,新生血管的形成亦然,血管刺激因素增强和(或)抑制因素减少使两者平衡失调即所谓的"血管生成开关".血管内皮生长因子(vascuar endothelial growth factor,VEGF)和色素上皮衍生因子(pigment epithelium-derived factor,PEDF) 作为血管牛成因子与血管抑制因子的一对典型代表,在糖尿病视网膜病变中的作用已逐渐被人们认识.本文就二者在糖尿病视网膜病变中作用的研究进展做一综述.并为DR的相关药物治疗提供思路.     

色素上皮衍生因子的高表达抑制视网膜炎症反应和新生血管化的实验研究

色素上皮衍生因子(pigment epithelium-derived factor,PEDF)属丝氨酸蛋白酶抑制因子,可以抑制新生血管的生成。为了探讨PEDF的高表达对眼内新生血管生成是否有影响,制作表达人PEDF的PEDF转基因鼠模型。在正常环境饲养下,PEDF转基因鼠的视网膜组织和视觉功能无异常表现。相反地,高氧环境下饲养的PEDF转基因鼠与正常野生鼠相比视网膜新生血管生成明显减少。同时也发现,与高氧环境下饲养的正常野生鼠相比,PEDF转基因鼠的视网膜血管渗漏较少,而紧密连接蛋白含量增加。这提示,PEDF对血-视网膜屏障有保护作用。此外,与高氧环境下饲养的正常野生鼠相比,PEDF转基因鼠的视网膜炎症因子含量较低。在激光诱导的脉络膜新生血管(choroidal neovascularization,CNV)模型中,与正常野生鼠相比,PEDF转基因鼠的CNV的面积较小;同时在正常野生鼠发现激光灼伤导致的促血管生成因子和炎症因子过表达,而PEDF转基因鼠未见促血管生成因子和炎症因子过表达。以上研究表明,PEDF的过度表达可以抑制高氧和激光诱导的CNV模型视网膜的炎症反应和新生血管化。PEDF转基因鼠对研究血管生成抑制因子在抑制糖尿病视网膜病变等疾病中新生血管化来说是一个较好的动物模型。     

Time-lapse imaging of vitreoretinal angiogenesis originating from both quiescent and mature vessels in a novel ex vivo system

PURPOSE: Diabetic retinopathy (DR) is an angiogenic disease that leads to severe visual loss. However, adequate animal models of vitreoretinal neovascularization in proliferative diabetic retinopathy (PDR) have not yet been described. The purpose of this study was to develop a novel ex vivo system for assessing vitreoretinal angiogenic processes that originate from both quiescent and mature vessels that could be observed with time-sequential imaging. METHODS: The retinas of 7- to 8-week-old mice were cultured for 4 days, with or without several growth factors with novel procedures, and immunohistochemistry was performed. The retinas from Tie2-GFP mice were cultured with vascular endothelial growth factor (VEGF), and time-sequential imaging of vitreoretinal angiogenesis was acquired. RESULTS: Vascular sprouts were induced by both VEGF and placenta growth factor, but not by insulin-like growth factor-1, basic fibroblast growth factor or angiopoietin-2. In explants with or without VEGF, perivascular mural cells were dissociated from endothelial cells, which is an important step during angiogenesis and in the progression of DR. Furthermore, use of time-lapse observations of retinal neovascularization events visualized that the first step in vascular sprout emergence from quiescent vessels was a single cell extension. The leading edges of a sprouting endothelial cell extended and retracted in a sequential manner. From newly formed vessels, additional vascular sprouts then emerged and new vessels fused to each other, resulting in vascular branching. CONCLUSIONS: Time-lapse imaging of this system visualized the dynamic process in vitreoretinal neovascularization from quiescent and mature vessels.     

Angiogenesis and retinal diseases

Angiogenesis is the process involving the growth of new blood vessels from preexisting vessels which occurs in both physiologic and pathological settings. It is a complex process controlled by a large number of modulating factors, the pro-and antiangiogenic factors. The underlying cause of vision loss in proliferative retinal diseases, such as age-related macular degeneration and proliferative diabetic retinopathy, are increased vascular permeability and choroidal neovascularization, and vascular endothelial growth factor (VEGF) plays a central role in this process. VEGF is produced in the eye by retinal pigment epithelium (RPE) cells and is upregulated by hypoxia. There are four major biologically active human isoforms, of which VEGF165 is the predominant in the human eye and appears to be the responsible for pathological ocular neovascularization. Besides being a potent and specific mitogen for endothelial cells, VEGF increases vascular permeability, inhibits endothelial cells apoptosis, and is a chemoattractant for endothelial cell precursors. VEGF is not the only growth factor involved in ocular neovascularization. Basic fibroblast growth factor (bFGF), angiopoietins, pigment epithelium-derived factor (PEDF), and adhesion molecules also play a role in the pro- and antiangiogenic balance. Advances in the understanding of the bases of pathological ocular angiogenesis and identification of angiogenesis regulators have enabled the development of novel therapeutic agents. Anti-VEGF antibodies have been developed for intravitreal use, and other approaches are currently under investigation. These new drugs may be powerful tools for the treatment of the leading causes of irreversible blindness in people over age 65.     

Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy

Although retinal neovascularization in proliferative diabetic retinopathy(PDR) is a major cause of legal blindness, its mechanism is not fully understood. In this study, we focused on the angiogenic activity of erythropoietin (Epo) and evaluated its potential role in treating retinal angiogenesis in PDR. METHODS: We measured Epo and vascular endothelial growth factor (VEGF) levels in the vitreous fluids of 73 PDR patients and 71 nondiabetic (NDM) patients. We evaluated Epo expression and regulation in retinal neovascularization with soluble Epo receptor. RESULTS: The vitreous Epo level was significantly higher in patients with PDR than in NDM patients. Multivariate logistic-regression analyses indicated that Epo and VEGF were independently associated with PDR and that Epo was more strongly associated with PDR than VEGF was. The blockade of Epo inhibited retinal neovascularization in vitro and in vivo. CONCLUSIONS: Our data suggest that Epo is a potent angiogenic factor that acts independently of VEGF during retinal angiogenesis in PDR.     

Rationale for combination therapies for choroidal neovascularization

PURPOSE: To provide a conceptual framework for the development and use of combination therapies for choroidal neovascularization secondary to age-related macular degeneration. DESIGN: Literature review, integration of data, and creation of hypothesis. METHODS: An assessment of angiogenesis, cancer therapy, and inflammation was performed as they may pertain to choroidal neovascularization. A conceptual framework was created in which therapies for choroidal neovascularization could be evaluated alone or in combination. RESULTS: Angiogenesis occurs because cells produce angiogenic stimuli to encourage blood vessels to develop. This growth of vessels involves an orchestrated interaction among many mediators offering opportunity to modulate or inhibit the entire process. A two-component model for choroidal neovascularization is proposed. The vascular component of choroidal neovascularization is comprised of vascular endothelial cells, endothelial cell precursors, and pericytes. The extravascular component, which by histopathology appears to be both the source of angiogenic stimuli and often the largest component volumetrically, is comprised of inflammatory, glial and retinal pigment epithelial cells, and fibroblasts. Tissue damage can be caused by either component. Each component can be targeted through as variety of monotherapies. Combination therapies offer the possibility of attacking one component in more than one way or by attacking both components simultaneously. CONCLUSIONS: The two-component model of choroidal neovascularization can be used to evaluate the mechanism of action and possible interactions of these agents in a conceptual framework. Extension of these ideas can help guide development of new treatment agents and approaches.     

Bevacizumab in glaucoma: a review

Recent research has shown that a large number of growth factors are responsible for neovascularization. Vascular endothelial growth factor has been identified as playing a key role in ocular angiogenesis. Bevacizumab, a humanized monoclonal antibody that binds to all isoforms of vascular endothelial growth factor, has shown promising results in regression of neovascularization. The use of bevacizumab has been reported extensively in various retinal pathologies, including proliferative diabetic retinopathy, cystoid macular edema, neovascular age-related macular degeneration, and neovascular glaucoma, but the clinical use in glaucoma is not yet clear. Glaucoma filtering surgery entails fashioning an external filter for aqueous drainage, and a prerequisite to its optimum functioning is a patent filtering bleb. Since fibroblast function and growth of new vessels is a component of healing of the bleb, there have been attempts to retard this healing by the use of bevacizumab. This article reviews current clinical studies documenting the use of bevacizumab in glaucoma.     

Herbimycin A inhibits angiogenic activity in endothelial cells and reduces neovascularization in a rat model of retinopathy of prematurity

The pathogenesis of retinopathy of prematurity involves dysregulated angiogenesis resulting in pre-retinal growth of new vessels. Inhibition of tyrosine kinase-dependent pro-angiogenic signals may provide a rational therapeutic approach to the reduction of pre-retinal neovascularization. Vascular endothelial growth factor stimulates endothelial cell mitogenesis, differentiation and migration, by binding and activating the receptor tyrosine kinases vascular endothelial growth factor receptor-1 and vascular endothelial growth factor receptor-2. One of the vascular endothelial growth factor receptor substrates implicated in vascular endothelial growth factor signal transduction is c-Src. The ability of herbimycin A, a c-Src-selective tyrosine kinase inhibitor, to inhibit vascular endothelial growth factor-induced bovine retinal microvascular endothelial cell proliferation and tube formation was investigated. The ability of the compound to inhibit pathologic angiogenesis was tested in a rat model of retinopathy of prematurity. Exposure of neonatal rats to oxygen concentrations cycling between 10 and 50% induced severe pre-retinal neovascularization in all rats. Some of the eyes of these variable oxygen-exposed rats were herbimycin A-injected or vehicle-injected 1 or 3 days post-oxygen exposure while some eyes were non-injected. All rats were sacrificed for assessment 6 days post-exposure. Herbimycin A inhibited both vascular endothelial growth factor-induced bovine retinal microvascular endothelial cell proliferation and capillary tube formation in a dose-dependent manner. Injection of herbimycin A into oxygen-treated rats 1 day post-oxygen exposure produced a 63% decrease in pre-retinal neovascularization relative to vehicle (P = 0.0029). There was a 41% decrease in pre-retinal neovascularization in herbimycin-injected eyes relative to vehicle-injected eyes 3 days post-oxygen (P = 0.031). Pre-retinal neovascularization was reduced in vehicle-injected eyes relative to non-injected eyes at both injection times. There were no significant differences in retinal vascular area between any of the experimental groups. Based on the results of this study, herbimycin A inhibits endothelial cell proliferation and tube formation at non-toxic concentrations and reduces pre-retinal neovascularization in a rat model of retinopathy of prematurity. Reduction of angiogenesis by the inhibition of tyrosine kinase activity may be a viable route to the development of effective chemotherapies applicable to eye disease.     

Ocular neovascularization. The Krill memorial lecture

The various vascular systems of the eye can undergo new vessel formation. In this presentation, I discuss new vessel growth in the cornea, lens, iris, ciliary body, choroid, retina, and optic nerve head. No single factor can explain all cases of ocular neovascularization; instead there are multiple factors which can affect the various susceptible vessels. Among the known vasculognic factors are: inflammation and its products, a hypoxic retina diffusable factor, the "tumor angiogenic factor," and possibly an aging factor. The different ocular beds possess differing sensitivity to the various vasculogenic stimuli; the iris and choroid being most sensitive and the retina and ciliary body least sensitive to such stimuli. Retinal neovascularization requires both a biochemical factor and a diseased retinal vascular bed for its induction. Ocular neovascularization is a dynamic process which requires a persisting stimulus or else the new vessels tend to regress. The normal eye seems to possess at least two antivasculogenic agents.     

分泌粒蛋白Ⅲ抗体治疗眼底新生血管的研究进展

分泌粒蛋白Ⅲ(SecretograninⅢ,Scg3/SgⅢ)是一个新近发现的血管生长因子,相关体内、体外研究已证实Scg3在眼底新生血管的形成中具有重要作用。近年来,将Scg3抗体应用于眼底新生血管的治疗也取得了一些进展,其作用机制与血管内皮生长因子(vascular endothelial growth factor,VEGF)不同,Scg3仅在病理性新生血管中表达,在正常血管中不表达,是一种新发现的具有高选择性表达的血管生长因子。本文从Scg3分子结构、信号传导通路以及其在眼底视网膜及脉络膜新生血管治疗中的最新进展进行了综述,旨在为视网膜及脉络膜新生血管的治疗提供一个新的治疗思路。     

血管内皮生长因子 A的选择性剪接与眼内新生血管的生成

眼内新生血管的生成是多种眼病致盲的重要原因.血管内皮生长因子A(VEGF-A)家族是促进眼内新生血管生成的关键因素,其通过调控病理性血管的发生和增加血管的通透性而起作用.VEGF-A依选择性剪接方式的不同,可形成2个蛋白家族,分别是具有促血管生成作用的VEGFxxx家族和具有抗血管生成作用的VEGFxxxb家族.VEGFxxxb家族蛋白在正常眼组织中均有表达,而在糖尿病性视网膜病变患者的眼组织中表达水平降低.VEGF165b是VEGFxxxb家族中最早分离出来且研究最为广泛的分子结构,其可以明显抑制视网膜前新生血管的生成,而对视网膜生理性血管的发生无抑制作用.随着对VEGFxxxb家族研究的逐步深入,选择性剪接调节VEGFxxx与VEGFxxxb两者之间的平衡,可作为糖尿病性视网膜病变、年龄相关性黄斑变性等眼内新生血管性疾病的治疗新策略.     

血管内皮生长因子 A的选择性剪接与眼内新生血管的生成

眼内新生血管的生成是多种眼病致盲的重要原因.血管内皮生长因子A(VEGF-A)家族是促进眼内新生血管生成的关键因素,其通过调控病理性血管的发生和增加血管的通透性而起作用.VEGF-A依选择性剪接方式的不同,可形成2个蛋白家族,分别是具有促血管生成作用的VEGFxxx家族和具有抗血管生成作用的VEGFxxxb家族.VEGFxxxb家族蛋白在正常眼组织中均有表达,而在糖尿病性视网膜病变患者的眼组织中表达水平降低.VEGF165b是VEGFxxxb家族中最早分离出来且研究最为广泛的分子结构,其可以明显抑制视网膜前新生血管的生成,而对视网膜生理性血管的发生无抑制作用.随着对VEGFxxxb家族研究的逐步深入,选择性剪接调节VEGFxxx与VEGFxxxb两者之间的平衡,可作为糖尿病性视网膜病变、年龄相关性黄斑变性等眼内新生血管性疾病的治疗新策略.