脈絡膜新生血管階段一

1、脈絡膜新生血管 CNV,CNV的發(fā)生機制,RPE-Bruch膜-脈絡膜毛細血管復合體改變對CNV的影響,C57BL/6J（B6） Laser-induced CNV,腹腔麻醉：0.5%戊巴比妥鈉 散瞳：托品酰胺苯腎上腺素 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.,細胞,新生血管形成過程,內皮細胞的活化（缺氧） (HIF-1)VEGF NO(血管舒張); 內皮細胞通透性增加，有利于血漿向組織擴散 血管外基質的降解 內皮細胞的增生、移行 新生血管的成熟,VEGF,bFGF,T-PA,u-PA,TNF-a,IL-1,MMP-1,MMP-3,上調,VEGF,NO cGMP,MAPK,bFGF,整合素avB3等,PDGF,aFGF,Ang及受體Tie-1,Tie-2,RPE對CNV的雙重調節(jié)功能,1.促進作用 生成促進血管內皮細胞增生和移行的VEGF,

3、FGF,TGF-a,TNF-a等等 誘導體內血管內皮細胞形成窗孔結構，影響新生血管的成熟 2.抑制作用 直接接觸抑制血管內皮細胞的移行 分泌抑制血管內皮細胞生長的物質：TGF-b,PEDF 釋放凝血酶原激活物抑制因子，使纖維酶原向纖溶酶的轉化受阻，細胞外基質不能降解,巨噬細胞,激光誘導CNV，第一天巨噬細胞出現，第三天達到高峰，5-7天后開始減少。,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,巨噬細胞+RPE,參與血管內皮生長因子誘發(fā)脈絡膜新生血管的信號通路,MAPK途徑 PI-3K-AKt/PKB途徑 鈣離子依賴性激

4、酶途徑 NO途徑,P38內皮細胞移行,VEGF誘導活化:ERK,JNK,PI-3K:CEC增生,ILK：內皮細胞增生和移行,轉錄因子,STAT3 NF-kappa-B HIF-1,STAT3,Signal transducer and transcription activator 退化期CNV的RPE細胞中，有STAT3的高表達，而在已纖維化的盤狀瘢痕中，STAT3的表達呈陰性，提示STAT3的活化與CNV的纖維化有關。,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受多種細胞內和細胞外的刺激如細胞因子，氧化劑自由基，紫外線照射，細菌性或病毒性產物激活的轉錄調節(jié)子。激活的NFB易位到細胞核中，并刺激參與多種生物功能的基因的表達。NFB的不適當活化已經與許多炎癥性疾病相關，而NFKB的持久

11、性抑制導致不適當的免疫細胞的發(fā)育或延緩細胞生長。,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. 缺氧適應性反應的主轉錄調節(jié)。在缺氧條件下，激活了40個基因，包括促紅細胞生成素，葡萄糖轉運，糖酵解酶，血管內皮生長因子，乳過氧化物酶，和其他基因，其蛋白產物增加氧氣傳遞或促進代謝適應低氧的轉錄。在胚胎血管生成，腫瘤血管生成和缺血性

17、疾病的病理生理學中起重要作用。,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):6197-206 IF:3.66 4.Influence of Dll4 via HIF-1-VEGF signaling on the angiogenesis of choroidal neovascularization under hypoxic conditi