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1、脉络膜新生血管 CNV,CNV的发生机制,RPE-Bruch膜-脉络膜毛细血管复合体改变对CNV的影响,C57BL/6J（B6） Laser-induced CNV,腹腔麻醉：0.5%戊巴比妥钠 散瞳：托品酰胺苯肾上腺素 激光：647.1 nm; 50mm spot size; 0.05 s duration; 360 mW. 1PD；3,6,9,12 oclock positions,Fundus fluorescein angiography,3 min after intraperitoneal injection of 0.3 mL of 2%fluorescein sodium wa
2、s injected into the intraperitoneal cavity of the mice.,细胞,新生血管形成过程,内皮细胞的活化（缺氧） (HIF-1)VEGF NO(血管舒张); 内皮细胞通透性增加，有利于血浆向组织扩散 血管外基质的降解 内皮细胞的增生、移行 新生血管的成熟,VEGF,bFGF,T-PA,u-PA,TNF-a,IL-1,MMP-1,MMP-3,上调,VEGF,NO cGMP,MAPK,bFGF,整合素avB3等,PDGF,aFGF,Ang及受体Tie-1,Tie-2,RPE对CNV的双重调节功能,1.促进作用 生成促进血管内皮细胞增生和移行的VEGF,
3、FGF,TGF-a,TNF-a等等 诱导体内血管内皮细胞形成窗孔结构，影响新生血管的成熟 2.抑制作用 直接接触抑制血管内皮细胞的移行 分泌抑制血管内皮细胞生长的物质：TGF-b,PEDF 释放凝血酶原激活物抑制因子，使纤维酶原向纤溶酶的转化受阻，细胞外基质不能降解,巨噬细胞,激光诱导CNV，第一天巨噬细胞出现，第三天达到高峰，5-7天后开始减少。,VEGF，MMP-9 蛋白水解酶（玻璃膜）,IL-1a,IL-1b,TNF-a IL-8,MCP-1,生成血管活性因子,巨噬细胞+RPE,参与血管内皮生长因子诱发脉络膜新生血管的信号通路,MAPK途径 PI-3K-AKt/PKB途径 钙离子依赖性激
4、酶途径 NO途径,P38内皮细胞移行,VEGF诱导活化:ERK,JNK,PI-3K:CEC增生,ILK：内皮细胞增生和移行,转录因子,STAT3 NF-kappa-B HIF-1,STAT3,Signal transducer and transcription activator 退化期CNV的RPE细胞中，有STAT3的高表达，而在已纤维化的盘状瘢痕中，STAT3的表达呈阴性，提示STAT3的活化与CNV的纤维化有关。,STAT3+CNV,1.A novel protective role for the innate immunity Toll-Like Receptor 3 (TLR3
5、) in the retina via Stat3. Mol Cell Neurosci. 2014 Sep 28;63C:38-48 IF:3.73 2.CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Mller glial cells. Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):E4520-9 IF:9.81 3.Toll-like receptor 3 (TLR3) protec
6、ts retinal pigmented epithelium (RPE) cells from oxidative stress through a STAT3-dependent mechanism. Mol Immunol. 2013 Jun;54(2):122-31 IF:3.0 4.Suppression of choroidal neovascularization through inhibition of APE1/Ref-1 redox activity. Invest Ophthalmol Vis Sci. 2014 Jun 26;55(7):4461-9 IF.3.66
7、5.IL-27 inhibits pathophysiological intraocular neovascularization due to laser burn. J Leukoc Biol. 2012 Feb;91(2):267-73 IF:4.3 6.Interleukin-6 receptor-mediated activation of signal transducer and activator of transcription-3 (STAT3) promotes choroidal neovascularization. Am J Pathol. 2007 Jun;17
8、0(6):2149-58 IF:4.6 7.Hyperglycaemia exacerbates choroidal neovascularisation in mice via the oxidative stress-induced activation of STAT3signalling inRPEcells. PLoS One. 2012;7(10):e47600. doi: 10.1371/journal.pone.0047600. Epub 2012 Oct 19,NF-kappa-B,NFKB is a transcription regulator that is activ
9、ated by various intra- and extra-cellular stimuli such as cytokines, oxidant-free radicals, ultraviolet irradiation, and bacterial or viral products. Activated NFKB translocates into the nucleus and stimulates the expression of genes involved in a wide variety of biological functions. Inappropriate
10、activation of NFKB has been associated with a number of inflammatory diseases while persistent inhibition of NFKB leads to inappropriate immune cell development or delayed cell growth. NFB受多种细胞内和细胞外的刺激如细胞因子，氧化剂自由基，紫外线照射，细菌性或病毒性产物激活的转录调节子。激活的NFB易位到细胞核中，并刺激参与多种生物功能的基因的表达。NFB的不适当活化已经与许多炎症性疾病相关，而NFKB的持久
11、性抑制导致不适当的免疫细胞的发育或延缓细胞生长。,NF-kappa-B,1.Roles for the ubiquitin-proteasome pathway in protein quality control and signaling in the retina: implications in the pathogenesis of age-related macular degeneration. Mol Aspects Med. 2012 Aug;33(4):446-66 IF:10.3 2.Macular pigment lutein is antiinflammatory i
12、n preventing choroidal neovascularization. Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2555-62 IF:5.53 3.IKK2 inhibition attenuates laser-induced choroidal neovascularization. PLoS One. 2014;9(1):e87530 IF:3.53 4.TNF- decreases VEGF secretion in highly polarized RPE cells but increases it in non-
13、polarized RPE cells related to crosstalk between JNK and NF-B pathways. PLoS One. 2013;8(7):e69994 IF:3.53 5.NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration. Invest Ophthalmol Vis Sci. 2013 Jan 7;54(1):
14、110-20 IF:3.66 6.Regulatory role of HIF-1alpha in the pathogenesis of age-related macular degeneration (AMD). Ageing Res Rev. 2009 Oct;8(4):349-58 IF:7.63 7.Roles of NFB-miR-29s-MMP-2 circuitry in experimental choroidal neovascularization. J Neuroinflammation. 2014 May 15;11:88 IF:4.9,HIF-1,Function
15、s as a master transcriptional regulator of the adaptive response to hypoxia. Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters,glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products i
16、ncrease oxygen delivery or facilitate metabolic adaptation to hypoxia. Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. 缺氧适应性反应的主转录调节。在缺氧条件下，激活了40个基因，包括促红细胞生成素，葡萄糖转运，糖酵解酶，血管内皮生长因子，乳过氧化物酶，和其他基因，其蛋白产物增加氧气传递或促进代谢适应低氧的转录。在胚胎血管生成，肿瘤血管生成和缺血性
17、疾病的病理生理学中起重要作用。,HIF-1,1.Decorin inhibits angiogenic potential of choroid-retinal endothelial cells by downregulating hypoxia-induced Met, Rac1, HIF-1 and VEGF expression in cocultured retinal pigment epithelial cells. Exp Eye Res. 2013 Nov;116:151-60 IF:3.02 2.Methallothionein-3 contributes to vascu
18、lar endothelial growth factor induction in a mouse model of choroidal neovascularization. Metallomics. 2013 Oct;5(10):1387-96 IF:3.98 3.Impacts of hypoxia-inducible factor-1 knockout in the retinal pigment epithelium on choroidal neovascularization. Invest Ophthalmol Vis Sci. 2012 Sep 14;53(10):6197
19、-206 IF:3.66 4.Influence of Dll4 via HIF-1-VEGF signaling on the angiogenesis of choroidal neovascularization under hypoxic conditions. PLoS One. 2011 Apr 19;6(4):e18481 IF:3.53 5.Inhibitory efficacy of hypoxia-inducible factor 1alpha short hairpin RNA plasmid DNA-loaded poly (D, L-lactide-co-glycolide) nanoparticles on choroidal neovascularization in a laser-induced rat model. Gene Ther. 2010 Mar;17(3):338-51 IF:4.20,