angiopoietins家族与角膜新生血管形成的关系

角膜新生血管形成是角膜疾患的难题之一,其发病机制尚未明确.血管生成素(Ang)与其受体Tie2结合后构成Ang/Tie2信号传导系统.该系统在血管生成与调节的过程中发挥重要作用.目前,眼科学界已取得一些新的关于Ang/Tie2信号系统在角膜新生血管形成方面的研究进展.本文旨在分析、归纳Ang家族及其受体的结构、功能以及Ang/Tie2信号系统在角膜新生血管发生机制中的作用.     

血管生成素与眼部新生血管的关系

血管生成素(angiopoietin,Ang)是特异性作用于血管内皮细胞的生长因子,主要由Ang-1和Ang-2组成;Tie2(tyrosinekinasethatcontainsim-munoglubin-likeloopsandepidermalgrowthfac-tor-similardomains2)是其共同受体。Ang-1促使血管成熟,维持血管稳定。Ang-2则拮抗Ang-1的作用,始动病理性新生血管形成。在眼部新生血管形成过程中Ang/Tie2受体途径起重要作用,抑制Ang/Tie2受体途径可以抑制眼部新生血管形成。     

血管生成素-2及其受体在脉络膜新生血管中的表达

目的研究血管生成素2(Ang2)及其受体Tie2在脉络膜新生血管(CNV)中的作用机制。方法应用氪激光诱导BN大鼠CNV,检测Ang2mRNA,Ang2和Tie2在CNV中的表达,探讨其作用。结果Ang2mRNA在正常BN大鼠视网膜无表达。光凝后7d,Ang2mRNA于视网膜神经节细胞层、内核层、外核层缺损区、视网膜和脉络膜血管内皮细胞的阳性染色密度最高(P<0.05),7d后变化差异不显著(P>0.05)。Ang2及受体与Ang2mRNA表达部位及趋势相同。Tie2在正常脉络膜血管内皮细胞表达。结论Ang2和Tie2结合,参与CNV形成。     

Ang/Tie-2信号传导系统与视网膜微血管形成

促血管生成素(angiopoietins,Ang)及其受体Tie-2构成的Ang/Tie-2信号传导系统对于血管生成(angiogenesis)过程中血管成熟与稳定、调控血管完整性具有重要意义。该家族不同因子对于血管生成作用不同,而且同一因子对于血管生成的作用也随条件的不同而改变。对于生理和病理状态下的视网膜微血管形成,Ang/Tie-2信号传导系统起到调节血管结构的持久稳定性,调节渗漏的作用,这对于糖尿病视网膜病变(diabeticretinopathy,DR)的治疗提供了一个重要的思路。     

不同分级的糖尿病视网膜病变患者血清血管生成素1和2比值变化

血管生成素(Ang)是继血管内皮生长因子(VEGF)后发现的另一类促血管形成因子.Ang家族中的Ang-1和Ang-2竞争性地作用于内皮细胞特异性酪氨酸激酶受体Tie-2并对血管起着相反的作用[1].其中,Ang-1起着促进血管成熟、抑制新生血管形成和减少血管渗漏的作用[2],而Ang-2则可以加重血管渗漏和新生血管形成从而加重视网膜病变[3].Ang-1和Ang-2之间的平衡和Ang/Tie-2体系决定了血管生成与稳定[4].出现新生血管是增生型糖尿病视网膜病变(PDR)的病理特征.已有较多研究报道Ang-2在糖尿病视网膜病变(DR)中明显升高[5],但少有涉及Ang-1与Ang-2的比值与DR关系的报道.我们对一组2型糖尿病(T2DM)患者的血清Ang-1、Ang-2和Tie-2含量进行检测,观察分析Ang-1与Ang-2的比值与DR的关系.现将结果报道如下.     

PIGF在湿性黄斑变性中的作用探讨

脉络膜新生血管是湿性黄斑变性( neovascularage-related macular degeneration,nAMD)的主要发病机制,而血管内皮生长因子( vascular endothelial growth factor,VEGF)促进新生血管的作用已受到广泛认可,目前针对VEGF不同靶点的药物已广泛运用于治疗 nAMD。胎盘生长因子( placental growth factor,PIGF)是抗VEGF的一个新靶点,与VEGF-A有协同作用,可促进新生血管,刺激内皮细胞迁移增殖,介导免疫炎症反应,且在已成熟血管上无表达,特异性较高。本文就PIGF在nAMD中的作用进行探讨。     

血管生成素1对视网膜新生血管形成的作用及其机制

视网膜缺血缺氧导致新生血管形成和渗漏是多种致盲性眼病的严重病理过程，是目前眼科研究的热点和难点。血管生成素1是近年来发现的重要新生血管生长调控因子，因其在新生血管的转归和促血管成熟稳定中的作用而日益受到重视，但血管生成素1在眼部尤其是视网膜的作用机制研究尚处于起步阶段。现就血管生成素1对视网膜新生血管数量及渗漏性、内皮细胞增生移行、壁细胞募集等的影响的研究现状进行综述，为视网膜新生血管的重建成熟提供新思路。（中华眼底病杂志，2007，23：149-152）     

胎盘生长因子在眼新生血管性疾病中的作用

胎盘生长因子(Placental growth factor,PIGF),是血管内皮生长因子(Vascular endothelial growth factor,VEGF)家族的成员之一,具有促进滋养细胞增殖、促进新生血管生成、介导免疫及炎症反应、调节造血等生物学作用.PIGF表达于血管内皮细胞,通过自分泌和旁分泌作用调节血管内皮细胞功能,在新生血管形成中起关键作用.PIGF特异性表达于病理性新生血管,在正常血管中不表达,较VEGF更具有特异性,因此抗PlGF治疗有可能成为靶向性治疗眼新生血管性疾病的新方向.     

基质细胞衍生因子-1与视网膜新生血管

视网膜新生血管是主要的致盲因素之一,目前发生机制尚不明确。基质细胞衍生因子-1（SDF-1）是新近发现的趋化因子,与趋化因子受体4（CXCR4）共同构成SDF-1/CXCR4轴。SDF-1/CXCR4参与了炎症反应、造血干细胞归巢及肿瘤侵袭。研究表明,SDF-1还能通过促进血管内皮细胞的迁移增生,招募内皮祖细胞,调节促血管生成因子等途径诱导新生血管生成,在视网膜新生血管的发生发展中发挥重要作用。就SDF-1/CXCR4的生物学功能、对促视网膜新生血管形成的机制及其在视网膜新生血管性疾病防治中的应用前景进行综述。     

贝伐单抗在角膜新生血管性疾病与翼状胬肉中的应用

贝伐单抗是近年来出现的新型血管生成靶向治疗药物,具有抑制血管内皮生长因子亚型,阻止血管渗漏和新生血管形成,抗纤维增生的作用,在治疗多种眼部新生血管相关性疾病中取得较好的疗效,本文就贝伐单抗在角膜新生血管性疾病与翼状胬肉中的应用作一综述.     

Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data

The angopoietin/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Ang/Tie) pathway is an emerging key regulator in vascular development and maintenance. Its relevance to clinicians and basic scientists as a potential therapeutic target in retinal and choroidal vascular diseases is highlighted by recent preclinical and clinical evidence. The Ang/Tie pathway plays an important role in the regulation of vascular stability, in angiogenesis under physiological and pathological conditions, as well as in inflammation. Under physiological conditions, angiopoietin-1 (Ang-1) binds to and phosphorylates the Tie2 receptor, leading to downstream signalling that promotes cell survival and vascular stability. Angiopoietin-2 (Ang-2) is upregulated under pathological conditions and acts as a context-dependent agonist/antagonist of the Ang-1/Tie2 axis, causing vascular destabilisation and sensitising blood vessels to the effects of vascular endothelial growth factor-A (VEGF-A). Ang-2 and VEGF-A synergistically drive vascular leakage, neovascularisation and inflammation, key components of retinal vascular diseases. Preclinical evidence suggests that modulating the Ang/Tie pathway restores vascular stabilisation and reduces inflammation. This review discusses how targeting the Ang/Tie pathway or applying Ang-2/VEGF-A combination therapy may be a valuable therapeutic strategy for restoring vascular stability and reducing inflammation in the treatment of retinal and choroidal vascular diseases.Subject terms: Mechanisms of disease, Medical research     

Colocalization of Tie2, angiopoietin 2 and vascular endothelial growth factor in fibrovascular membrane from patients with retinopathy of prematurity

PURPOSE: The tyrosine kinase receptor Tie2 and its ligands, the angiopoietins (Angs), play important roles in vascular integrity and neovascularization, modulating vascular endothelial growth factor (VEGF) activity. To elucidate the potential role of Angs and the Tie2 system in retinopathy of prematurity (ROP), we have investigated the expression of Angs, Tie2 and VEGF within fibroproliferative membranes in ROP. METHODS: Fibroproliferative membranes were obtained from 38 cases with stage 5 ROP at the time of vitrectomy. Membranes were fixed in formalin and embedded in paraffin. Each specimen was serially sectioned for immunohistochemistry. Polyclonal antibodies specific for Ang1, Ang2, Tie2 and VEGF were used for immunostaining. Immunoreactivity for von Willebrand factor (factor VIII) was also assessed to confirm the identity of vascular endothelial cells. RESULTS: Positive staining for Tie2 was observed in 23 of 38 specimens (60.5%). Tie2 was localized in vascularized regions of fibrovascular membranes and was co- expressed with VEGF and factor VIII. Ang2 stained positively in 18 of 38 (47.3%) serial sections where Tie2 was present, and was also co-expressed with VEGF and factor VIII. Ang1 was not generally observed in these specimens (3/38). CONCLUSIONS: VEGF and Ang2-Tie2 interactions may play an important role in the pathogenesis of ROP.     

Expressions of angiopoietins and Tie2 in human choroidal neovascular membranes.

PURPOSE: To elucidate the potential role of angiopoietins and the Tie2 system in choroidal neovascularization. METHODS: Surgically excised choroidal neovascular membranes (CNVMs) were obtained at vitrectomy from five eyes with age-related macular degeneration, three eyes with idiopathic neovascular maculopathy, and two eyes had degenerative myopia and two eyes had angioid streaks. Light microscopic immunohistochemistry was performed to detect cytokines such as vascular endothelial growth factor (VEGF), Ang1, and Ang2 and cellular components such as retinal pigment epithelial (RPE) cells, macrophages, and endothelial cells. Immunofluorescent double staining using confocal microscopy was performed to identify the cell types that secrete specific cytokines. RESULTS: Ang1 and Ang2 were positive in all surgically excised CNVMs, regardless of the primary disease. Double staining revealed that many of the cytokeratin, CD68 and factor VIII positive cells also had Ang1 and Ang2 immunoreactivities. In contrast to Ang1, Ang2 immunoreactivity tends to be higher in the highly vascularized regions of many CNVMs, and the localization was very similar to that of VEGF staining. Almost all vascular structures had prominent immunoreactivity for Tie2, which was confirmed by double staining for Tie2 and factor VIII. Tie2 immunoreactivity was also observed in the RPE monolayer and in pigmented, polygonal, and fibroblast-like cells in the stroma. CONCLUSIONS: Present findings that Ang2 and VEGF are co-upregulated and that Tie2 is expressed in a variety of cell types in CNVMs further support a crucial role of the interaction between VEGF and Ang2 in pathologic angiogenesis of CNVM formation.     

上皮-间质转化在视网膜下纤维化发病机制中的研究进展

视网膜下纤维化(SRFi)被定义为视网膜内或视网膜下混合的纤维血管结构，本质是新生血管性年龄相关性黄斑变性(nAMD)中脉络膜新生血管形成后伤口过度愈合的结果，这是导致nAMD患者终末期视力丧失的主要原因。nAMD患者终末期视网膜色素上皮细胞向上皮-间质细胞转化的过程被认为是影响SRFi形成的主要细胞基础。针对SRFi中上皮-间质转化的相关细胞及分子机制研究可能是未来终末期nAMD疾病防治的重要发展方向。     

新生血管性年龄相关性黄斑变性患者玻璃体内注射抗血管内皮生长因子药物治疗进展

年龄相关性黄斑变性是引起50岁以上人群视力不可逆性损伤的主要原因之一，新生血管性年龄相关性黄斑变性（neovascular age-related macular degeneration,nAMD）也称湿性年龄相关性黄斑变性（wet age-related macular degeneration,wAMD），是其晚期阶段，可导致最严重的视力丧失。血管内皮生长因子（vascular endothelial growth factor,VEGF）是脉络膜新生血管和视网膜渗漏形成的主要因素，抗VEGF治疗是目前唯一实现多数患者视力改善并且停止疾病进展的治疗方法，因此玻璃体内注射抗VEGF药物已经成为wAMD一线治疗方法。用于临床治疗wAMD的抗VEGF药物主要有哌加他尼、贝伐单抗、雷珠单抗、阿柏西普和康柏西普。治疗方案有固定式、按需式以及治疗和延长式治疗方案。Brolucizumab和abicipar pegol是2种新的抗VEGF药物，正处于3期临床试验阶段。本文对以上药物治疗wAMD的研究进展进行综述。