脉络膜新生血管阶段一课件

脉络膜新生血管CNVCNV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Fundusfluoresceinangiography3minafterintraperitonealinjectionof0.3mLof2%fluoresceinsodiumwasinjectedintotheintraperitonealcavityofthemice.细胞名称细胞株内皮细胞themurinecelllineb-End3;humanumbilicalveinendothelialcells;Choroid-retinalendothelialcellline

RPEhumancelllineARPE-19; 巨噬细胞themurinecelllineRAW264.7新生血管形成过程内皮细胞的活化（缺氧）(HIF-1)VEGFNO(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,bFGFT-PA,u-PATNF-a,IL-1MMP-1,MMP-3上调VEGFNOcGMPMAPKbFGF,整合素avB3等PDGF,aFGF,Ang及受体Tie-1,Tie-2RPE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,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酶途径NO途径PI-3K:CEC增生ILK：内皮细胞增生和移行转录因子STAT3NF-kappa-BHIF-1STAT3Signaltransducerandtranscriptionactivator

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+CNV1.AnovelprotectiverolefortheinnateimmunityToll-LikeReceptor3(TLR3)intheretinaviaStat3.MolCellNeurosci.2014Sep28;63C:38-48IF:3.732.CNTF-mediatedprotectionofphotoreceptorsrequiresinitialactivationofthecytokinereceptorgp130inMüllerglialcells.ProcNatlAcadSciUSA.2013Nov19;110(47):E4520-9IF:9.813.Toll-likereceptor3(TLR3)protectsretinalpigmentedepithelium(RPE)cellsfromoxidativestressthroughaSTAT3-dependentmechanism.MolImmunol.2013Jun;54(2):122-31IF:3.04.SuppressionofchoroidalneovascularizationthroughinhibitionofAPE1/Ref-1redoxactivity.InvestOphthalmolVisSci.2014Jun26;55(7):4461-9IF.3.66

5.IL-27inhibitspathophysiologicalintraocularneovascularizationduetolaserburn.JLeukocBiol.2012Feb;91(2):267-73IF:4.36.Interleukin-6receptor-mediatedactivationofsignaltransducerandactivatoroftranscription-3(STAT3)promoteschoroidalneovascularization.AmJPathol.2007Jun;170(6):2149-58IF:4.67.Hyperglycaemiaexacerbateschoroidalneovascularisationinmiceviatheoxidativestress-inducedactivationofSTAT3

signallingin

RPE

cells.PLoSOne.2012;7(10):e47600.doi:10.1371/journal.pone.0047600.Epub2012Oct19NF-kappa-BNFKBisatranscriptionregulatorthatisactivatedbyvariousintra-andextra-cellularstimulisuchascytokines,oxidant-freeradicals,ultravioletirradiation,andbacterialorviralproducts.ActivatedNFKBtranslocatesintothenucleusandstimulatestheexpressionofgenesinvolvedinawidevarietyofbiologicalfunctions.InappropriateactivationofNFKBhasbeenassociatedwithanumberofinflammatorydiseaseswhilepersistentinhibitionofNFKBleadstoinappropriateimmunecelldevelopmentordelayedcellgrowth.

NFκB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NFκB易位到细胞核中，并刺激参与多种生物功能的基因的表达。NFκB的不适当活化已经与许多炎症性疾病相关，而NFKB的持久性抑制导致不适当的免疫细胞的发育或延缓细胞生长。

HIF-1

Functionsasamastertranscriptionalregulatoroftheadaptiveresponsetohypoxia.Underhypoxicconditions,activatesthetranscriptionofover40genes,includingerythropoietin,glucosetransporters,glycolyticenzymes,vascularendothelialgrowthfactor,HILPDA,andothergeneswhoseproteinproductsincreaseoxygendeliveryorfacilitatemetabolicadaptationtohypoxia.Playsanessentialroleinembryonicvascularization,tumorangiogenesisandpathophysiologyofischemicdisease.

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疾病的病理生理学中起重要作用。

HIF-11.Decorininhibitsangiogenicpotentialofchoroid-retinalendothelialcellsbydownregulatinghypoxia-inducedMet,Rac1,HIF-1αandVEGFexpressionincoculturedretinalpigmentepithelialcells.ExpEyeRes.2013Nov;116:151-60IF:3.022.Methallothionein-3contributestovascularendothelialgrowthfactorinductioninamousemodelofchoroidalneovascularization.Metallomics.2013Oct;5(10):1387-96IF:3.983.Impactsofhypoxia-induciblefactor-1knockoutintheretinalpigmentepitheliumonchoroidalneovascularization.InvestOphthalmolVisSci.2012Sep14;53(10):6197-206IF:3.664.InfluenceofDll4viaHIF-1α-VEGFsignalingontheangiogenesisofchoroidalneovascularizationunderhypoxicconditions.PLoSOne.2011Apr19;6(4):e18481IF:3.535.Inhibitor