2. 复旦大学附属中山医院厦门医院眼科, 厦门 361015
2. Department of Ophthalmology, Zhongshan Hospital (Xiamen Branch), Fudan University, Xiamen 361015, Fujian, China
眼部病理性新生血管相关疾病可造成视力下降,严重者视力丧失。其中,血管新生性年龄相关性黄斑变性(neovascular age-related macular degeneration,nAMD)已经成为世界范围内老年人眼盲的主要原因[1],而糖尿病视网膜病变在中青年人群致盲原因中占据首位[2]。
Wnt/β-catenin信号通路能够调控眼部病理性新生血管的发生发展。Wnt/β-catenin信号通路在进化过程中高度保守,有促进胚胎发育、维持组织稳态的作用。哺乳动物体内的Wnt/β-catenin信号通路主要由细胞膜Wnt、胞浆中β-catenin及细胞核中靶基因组成[3-4]。研究[5]表明,Wnt/β-catenin信号通路的靶基因大多具有组织或发展阶段特异性,在中枢神经系统的血管新生、血脑屏障及血-视网膜屏障的正常维持等生理过程中起到重要的调控作用。本文总结Wnt/β-catenin信号通路在病理性血管新生过程中的作用,探讨调控病理性血管新生的机制以及作为治疗靶点的潜在价值。
1 病理性新生血管性眼病眼部病理性新生血管可以发生在角膜、虹膜、黄斑、视网膜等部位,常可导致不可逆的视功能损伤。
1.1 眼前段新生血管生理情况下角膜并无血管结构,缺氧、感染或创伤等病理情况会造成血管生成因子和抑制因子失衡,导致角膜新生血管形成,影响角膜的正常形态和功能[6-7]。眼部特别是眼后段缺血时,血管内皮生长因子(vascular endothelial growth factor,VEGF)释放导致虹膜及房角新生血管形成,通过多种机制引起新生血管性青光眼,表现为严重的视功能障碍、高眼压引起的剧烈眼痛和头痛,严重影响患者生活质量[8]。
1.2 黄斑新生血管(macular neovascularization,MNV)MNV又称脉络膜新生血管(choroidal neovascularization, CNV),可导致中心视力下降、固定黑影、视物变形等[9]。年龄相关性黄斑变性(age-related macular degeneration,AMD)分为干性和湿性。湿性AMD(wAMD)是主要的MNV眼病之一,又称为nAMD,主要表现为黄斑区血管新生而导致组织出血、水肿,以及光感受器损伤。病理性近视、脉络膜炎等多种变性和炎症类疾病可导致MNV形成,进而严重损伤患者的中心视力。
1.3 视网膜新生血管视网膜是全身代谢活动最旺盛的区域之一,全身性的代谢性疾病会对视网膜血管产生影响,表现为视网膜血管新生,主要包括家族性渗出性玻璃体视网膜病变(familial exudative vitreoretinopathy,FEVR)、早产儿视网膜病变(retinopathy of prematurity, ROP)和糖尿病视网膜病变(diabetic retinopathy, DR)等[3]。遗传性视网膜新生血管疾病多存在基因突变所致的视网膜血管发育异常;非遗传性多由缺氧缺血、高血糖等内环境异常所致。视网膜新生血管及纤维血管膜的形成、增生可导致视网膜玻璃体出血、视网膜脱离等严重后果。
目前临床上多用抗VEGF药物(如雷珠单抗、康柏西普、阿柏西普等)来治疗病理性新生血管性眼病。然而,部分患者对抗VEGF药物应答欠佳[10],抗VEGF药物可能加重玻璃体视网膜增生牵引[11],长期使用可导致神经毒性及眼内炎、视网膜脱离、葡萄膜炎等其他眼部并发症[12-13]。因此,寻找眼部病理性血管新生发生过程中新的靶点及治疗手段是当下值得关注的问题。Wnt信号通路在多种病理性新生血管性眼病中起到关键的调控作用,靶向Wnt的治疗可能成为治疗此类疾病的新方法。
2 Wnt/β-catenin信号通路在眼部发育过程中的生物学功能在眼内,Wnt/β-catenin信号通路能够影响视网膜发育。在眼球发育的视杯阶段,Wnt/β-catenin信号通路的失活将导致视网膜色素上皮(retinal pigment epithelium,RPE)转分化为神经视网膜细胞,这种效应在RPE背侧更为明显,提示Wnt/β-catenin信号通路对视网膜极性的维持具有重要作用[14-16]。Wnt/β-catenin信号通路同时也介导视网膜血管形成[4, 17],NDP、FZD4、LRP5等Wnt/β-catenin信号通路相关基因突变可导致眼部血管发育缺陷[18],Wnt基因信号缺失所致视网膜血管形成障碍并不能被缺氧诱导的VEGF表达增加所逆转[19]。敲除Wnt膜受体LRP5基因的小鼠也出现了严重的视网膜血管缺陷,表现为发育过程中视网膜血管过度形成,在成年期这种缺陷主要表现为视网膜缺血以及血管新生[20]。此外,Wnt/β-catenin信号通路在角膜、巩膜、晶状体等其他眼部结构的发育过程中也起到重要作用[21-23]。
Wnt/β-catenin信号通路能够协调内皮细胞行为进而控制血管发生[24]。Wnt的多种配体可通过旁分泌的方式调控血管内皮细胞功能,如巨噬细胞分泌的Wnt7b能够介导玻璃体血管消退中内皮细胞凋亡[25]。在许多类型的血管胚胎发育过程中发现Wnt信号的激活[26]。内皮β-catenin缺失会损害胚胎脉管系统的发育,导致有缺陷的血管重塑和弥漫性出血,从而导致胚胎发育早期阶段死亡[27],表明Wnt/β-catenin信号通路在血管发生的早期阶段起重要作用。
3 Wnt/β-catenin信号通路的调节机制β-catenin是Wnt/β-catenin信号通路的核心成分,信号传递的最终效应都依赖β-catenin的表达变化来实现,其C端和N端都可以通过与不同信号转导介质的结合激活对靶基因转录的调控[3]。Wnt/β-catenin信号通路未激活时,胞质中的β-catenin与由糖原合成激酶3β(glycogen synthase kinase-3β,GSK-3β)、轴蛋白Axin1/2和人腺瘤性结肠息肉病(adenomatous polyposis coli,APC)蛋白组成的多蛋白破坏复合体结合后被磷酸化,为泛素E3连接酶βTrCP创造结合位点,继而通过胞质中的蛋白酶体发生泛素化[28]。细胞膜上的Wnt及其受体LRP5/6与脂质结合时,信号通路被激活,轴蛋白降解,GSK-3β活性被抑制,解除磷酸化的β-catenin由胞质向核内转移,并在核内与T淋巴细胞特异性转录因子(T-cell transcription factor,TCF)结合,形成靶基因的转录激活子,调控其下游基因(cyclin D1,c-Myc,PDK1,MCT-1等)的表达[29](图 1)。
此外,GSK-3β也是蛋白激酶B(protein kinase B,PKB/AKT)的亚基,因此AKT能够通过磷酸化GSK-3β蛋白链的第9位丝氨酸残基灭活GSK-3β[30],增加胞质中β-catenin的浓度。蛋白磷酸酶2A(phosphatase 2A,PP2A)能够调控这一过程,也可以直接介导β-catenin在第37位丝氨酸及41位苏氨酸的去磷酸化[31],活化的β-catenin由胞质进入胞核内,启动Wnt下游靶基因的表达。
4 Wnt/β-catenin信号通路调控眼部病理性血管新生在形成病理性新生血管的脉络膜组织中,β-catenin在血管内皮细胞中富集,提示Wnt/β-catenin信号通路可以通过对血管内皮细胞的直接调控影响病理性血管新生[32-33]。Hu等[34]在激光诱导的CNV小鼠模型的视杯组织中发现,β-catenin及其受体LRP6过表达,而注射LRP6单克隆抗体Mab2F1的CNV小鼠模型组织中LRP6表达水平下降,胞浆中β-catenin的含量也随之降低,眼底荧光素血管造影结果也显示注射Mab2F1后小鼠眼底病灶的荧光素渗漏减少,表明Wnt/β-catenin信号通路参与调控MNV的形成与进展。Qiu等[35]在角膜新生血管发生过程中也检测到Wnt信号通路相关分子表达量的变化,抑制Wnt/β-catenin信号通路也能够抑制角膜血管新生的进展。
4.1 缺氧诱导因子(hypoxia-inducible factors, HIFs)调控眼部病理性血管新生HIFs包括HIF-1、HIF-2及HIF-3,是由对细胞内氧浓度敏感的α亚单位和稳定的β亚单位构成的异二聚体[36]。氧含量正常时,异二聚体处于解离状态,不具有生物学功能;缺氧条件下HIFs稳定性增加,由胞质进入核内,引起下游靶基因(包括VEGF-A、TGF-β3等)的表达,而这些靶基因在细胞适应性代谢改变、细胞生长、增殖及血管新生等过程中起关键作用[37]。HIF-1α增加能够激活数种糖酵解相关酶,如丙酮酸脱氢酶激酶(pyruvate dehydrogenase kinase, PDK)。PDK可使丙酮酸脱氢酶(pyruvate dehydrogenase complex, PDH)磷酸化并失活,并活化乳酸脱氢酶A(lactate dehydrogenase A, LDH-A),将胞质中糖酵解产生的丙酮酸转化为乳酸,阻断丙酮酸向乙酰CoA转化的过程,使得进入三羧酸循环的丙酮酸大量减少,而导致乳酸在胞内堆积。细胞内HIF-1α及乳酸浓度的增加均会引起促血管生成因子(如VEGF)表达上调[38-39],进而导致眼部新生血管的形成。
4.2 Wnt/β-catenin信号通路活化影响HIFs表达Wnt/β-catenin信号通路的活化能够诱导信号转导及转录激活蛋白3(signal transducers and activators of transcription 3,STAT3)磷酸化,STAT3直接与β-catenin/TCF复合物结合,通过真核生物DNA的翻译启动子4E-结合蛋白1(4E-binding protein 1,4E-BP1)激活HIF-1α,并上调Wnt/β-catenin信号通路的靶基因c-Myc及细胞周期因子D1(cyclin D1)的转录,c-Myc及cyclin D1又能进一步增加HIF-1α的表达[4]。在正常氧含量情况下,白细胞介素6(IL-6)或白血病抑制因子(leukemia inhibitory factor,LIF)也能够引起上述效应。
同时,Wnt/β-catenin信号通路活化后,β-catenin在核内浓度的增加能够引起细胞膜上的表皮生长因子受体(epidermal growth factor receptor,EGFR)及受体酪氨酸激酶(receptor tyrosine kinase,RTK)的激活,以此激活PI3K/AKT通路,继而引起4E-BP1和STAT3在转录水平上调HIF-1α的表达[40]。激活的EGFR也能够通过视网膜中光感受器表达的丙酮酸激酶同工酶M2(pyruvate kinase isozyme type M2,PKM2)正反馈调节诱导β-catenin及cyclin D1的表达上调,进一步增加HIF-1α及下游VEGF的表达[41](图 2)。
4.3 Wnt/β-catenin信号通路通过其他机制影响眼部血管新生炎症在AMD疾病发展过程中有着重要作用。在体外培养的RPE细胞中,肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)能够诱导MNV病变处产生更多的活性氧(reactive oxygen species,ROS),继而刺激多种炎症因子的释放,并促进RPE的氧化应激,同时TNF-α还能上调VEGF的表达[42]。抑制TNF-α的主要转录因子NF-κB后,RPE中VEGF的表达不受影响[43]。进一步研究发现,RPE中VEGF表达的增加是由TNF-α诱导的ROS生成和其后的β-catenin转录和核激活所致,且阻断Wnt/β-catenin信号通路后眼底病变的改善与抑制TNF-α等炎症因子相关基因的表达有关,提示在眼部炎症因子对病理性血管新生的调控可能通过Wnt/β-catenin信号通路实现[44-45]。
5 Wnt调节剂对病理性血管新生性眼病的潜在治疗价值研究[45]表明,在小鼠氧诱导视网膜病变模型中,Wnt/β-catenin信号通路共受体LRP5的抗体激动剂与抗VEGF药物都能够减少视网膜病理性新生血管面积,且靶向抑制Wnt/β-catenin信号通路并不会影响内皮细胞对于抗VEGF药物的敏感性。患者对抗VEGF治疗的应答欠佳可能是因为体内VEGF水平大于抗VEGF,即VEGF记忆,而靶向抑制Wnt可能有消除VEGF记忆的作用[45-46]。
5.1 KallistatinKallistatin是丝氨酸蛋白酶抑制剂(SERPIN)家族中的一种内源性抗血管新生和抗炎因子,与LRP6结合后可以抑制Wnt/β-catenin信号通路[47]。与非AMD受试者相比,AMD患者血浆中的Kallistatin水平降低。另一方面,其他的Wnt信号调节剂,如WIF-1和DKK3在nAMD患者的房水中显著增加,而DKK1水平在nAMD患者的循环中降低[48]。抑制nAMD患者异常激活的Wnt/β-catenin信号通路可能是治疗或抑制MNV病变进展的潜在方法。
5.2 伊利马奎诺酮(ilimaquinone,IQ)IQ是一种从海绵生物Hippiospongia metachromia中分离出的Wnt/β-catenin信号通路拮抗剂,具有抗HIV病毒、抗菌、抗炎和抗癌等作用[49]。近期研究[50]表明,IQ能够在nAMD中起到抗血管新生的作用。在ARPE-19细胞的体外实验中证明了IQ是通过下调Snail(内皮粘连因子E-cadherin的转录抑制物)的表达水平来阻断Wnt诱导的上皮间质转化(EMT)过程。在人脐静脉内皮细胞(human umbilical vein endothelial cell, HUVEC)中,IQ可以促进抑癌基因p53在392位点丝氨酸的磷酸化,增加其稳定性,从而抑制HUVEC细胞增殖。在激光处理的MNV家兔模型中,眼表滴入或腹腔注射IQ均可剂量依赖性地减小MNV病灶体积及血管渗漏。口服IQ的疗效在小鼠MNV模型中也得到了验证,且治疗效果与阿柏西普(一种重组的抗VEGF药物,目前临床上广泛用于nAMD的一线治疗)相似[50]。
5.3 过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptor γ,PPARγ)PPARγ是一种配体激活的转录因子,具有抗血管生成作用[51]。PPARγ的激活与Wnt/β-catenin信号通路的抑制相关:PPARγ激动剂可以下调β-catenin的表达水平,减少胞质中β-catenin的累积,能够抑制Wnt靶基因和下游通路的激活[44],体外实验[52]也证明PPARγ激动剂可以降低VEGF的表达,延缓视网膜内皮细胞的增生、迁移和血管新生。
5.4 其他Wnt调节剂作用于Wnt/β-catenin信号通路其他信号传导环节的物质,如维生素D、β-catenin/TCF抑制剂、转录共激活子的拮抗剂等被证明具有抑制肿瘤细胞增殖的效果[53],对寻找nAMD及其他眼部新生血管相关疾病的新治疗手段具有启发意义。
综上所述,Wnt/β-catenin信号通路在细胞的多种生理病理过程中起到重要的调控作用,其异常失活或过度激活都会导致细胞代谢过程发生改变,进而推动疾病的进展。目前的研究已经证明Wnt/β-catenin信号通路在眼部病理性血管新生的过程中起重要的调控作用。Wnt抑制剂能够抑制疾病进展,有望成为治疗眼部及其他部位相关疾病的潜在方法。
利益冲突:所有作者声明不存在利益冲突。
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