Subretinal fibrosis secondary to neovascular age-related macular degeneration:mechanisms and potential therapeutic targets

Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.

Nomogram for predicting short-term response to anti-vascular endothelial growth factor treatment in neovascular age-related macular degeneration:An observational study

BACKGROUND Anti-vascular endothelial growth factor(anti-VEGF)therapy is critical for managing neovascular age-related macular degeneration(nAMD),but understanding factors influencing treatment efficacy is essential for optimizing patient outcomes.AIM To identify the risk factors affecting anti-VEGF treatment efficacy in nAMD and develop a predictive model for short-term response.METHODS In this study,65 eyes of exudative AMD patients after anti-VEGF treatment for≥1 mo were observed using optical coherence tomography angiography.Patients were classified into non-responders(n=22)and responders(n=43).Logistic regression was used to determine independent risk factors for treatment response.A predictive model was created using the Akaike Information Criterion,and its performance was assessed with the area under the receiver operating characteristic curve,calibration curves,and decision curve analysis(DCA)with 500 bootstrap re-samples.RESULTS Multivariable logistic regression analysis identified the number of junction voxels[odds ratio=0.997,95%confidence interval(CI):0.993-0.999,P=0.010]as an independent predictor of positive anti-VEGF treatment outcomes.The predictive model incorporating the fractal dimension,number of junction voxels,and longest shortest path,achieved an area under the curve of 0.753(95%CI:0.622-0.873).Calibration curves confirmed a high agreement between predicted and actual outcomes,and DCA validated the model's clinical utility.CONCLUSION The predictive model effectively forecasts 1-mo therapeutic outcomes for nAMD patients undergoing anti-VEGF therapy,enhancing personalized treatment planning.

Choroidal structural changes determined by the binarization method after intravitreal aflibercept treatment in neovascular age-related macular degeneration

AIM:To assess the choroidal structural alterations after intravitreal injection of aflibercept in neovascular agerelated macular degeneration(n AMD).METHODS:Fifty eyes with treatment-naive n AMD were evaluated at baseline,3^(rd),and 12^(th) month.Fifty eyes of 50 healthy subjects were also included as controls.Choroidal thickness(CT)was measured in the subfoveal region.Total circumscribed choroidal area(CA),luminal area(LA),stromal area(SA),and choroidal vascularity index(CVI)was calculated using Image J.RESULTS:At baseline,subfoveal CT was increased in n AMD patients compared to controls(P=0.321).Eyes with n AMD had a significantly increased total circumscribed CA and SA(P=0.041,0.005,respectively).The CVI was decreased(P=0.038).In the 3^(rd) month,the subfoveal CT,LA,and CVI revealed a decrease(P=0.005,P=0.039,0.043,respectively).In the 12th month,subfoveal CT,LA,and CVI were decreased in comparison to baseline measures(P<0.001,0.006,0.010,respectively).CONCLUSION:Significant structural alterations are found after intravitreal aflibercept treatment during the 12-month follow-up,in particular at the third month,in eyes with n AMD.

Predictors of visual outcome in eyes with choroidal neovascularization secondary to age related macular degeneration treated with intravitreal bevacizumab monotherapy

AIM:To evaluate the predictors of visual improvement in eyes with naive choroidal neovascularization secondary to age-related macular degeneration (CNV -AMD) treated with intravitreal bevacizumab (IVB) monotherapy. METHODS:Fifty eyes with naive CNV-AMD with pretreatment best-corrected visual acuity (BCVA) better than 20/200 and treated with IVB monotherapy were evaluated. Several variables including age, sex, pre-treatment BCVA, CNV type and lesion size on fluorescein angiogram as well as SD-OCT parameters including pre-treatment central macular thickness (CMT), inner-segment/outer-segment (IS/OS) junction integrity, and external limiting membrane (ELM) integrity were analyzed to predict visual outcome.RESULTS:On univariate regression, pretreatment ELM damage was associated with less visual improvement after treatment (P =0.0145). However, ELM damage predicted only 10% of the visual outcome. On multivariate regression, pretreatment BCVA, IS/OS junction, and ELM integrity on SD-OCT were the significant predictors for the treatment effect and together predicted 37% of visual improvement. CONCLUSION:Pretreatment BCVA, ELM and IS/OS junction integrity on SD-OCT are of significant value inpredicting the visual improvement in naive wet AMD patients treated with IVB monotherapy.

Evaluation of fundus autofluorescence patterns in age-related macular degeneration

AIM： To study the various morphological patterns of fundus autofluorescence （FAF） images in patients with age-related macular degeneration （AMD） in Indian population.METHODS： Totally 179 eyes of 104 patients with clinical diagnosis of AMD were recruited into the study. Autofluorescence images were captured using confocal scanning laser ophthalmoscope and the patterns of FAF were classified.RESULTS： Of 179 eyes, 27 （15.08%） were early AMD, 58 （32.41%） were intermediate AMD, 94 eyes （52.51%） were late AMD. Of 94 eyes with late AMD, 79 （84.04%） were neovascular AMD and 15 （15.96%） were central geographic atrophy. In eyes with early and intermediate AMD, 9 patterns of FAF were noted. Six patterns （normal, minimal change, focal increased, patchy increased, linear, reticular） were similar to that in the published classification. Two patterns （lacelike and speckled） described in the published classification were not found. Three new patterns （focal hypo-fluorescence, patchy hypo-fluorescence, mixed focal hypo-fluorescence and hyper-fluorescence） were detected. In eyes with neovascular AMD, 6 morphological patterns of FAF were noted. Two patterns （mixed hypo-fluorescence and hyper-fluorescence, central hypo-fluorescence with hyper-fluorescent rim） were similar to that in published classification. Two patterns （normal, near normal or normal background fluorescence in the centre of hypo-fluorescent area） described in the published classification were not found. Four new patterns （minimal change, hypo-fluorescent patch, central hypo-fluorescence with surrounding reticular, bull’s eye） were recognized. In eye with central geographic atrophy 5 morphological patterns were noted and these were similar to that in published classification.CONCLUSION： Phenotypic differences in the pattern of FAF exist in the study population compared to existing classification systems.

Comparison of visual acuity outcomes between ranibizumab and bevacizumab treatment in neovascular age-related macular degeneration

AIM: To compare visual acuity (VA) outcomes between intravitreal injection of bevacizumab and ranibizumab in the treatment of neovascular age-related macular degeneration (AMD). METHODS: We conducted a consecutive, retrospective case series study in patients with newly diagnosed all type choroidal neovascularization (CNV) secondary to AMD who received an intravitreal injection of bevacizumab (1.25mg) or ranibizumab (0.3mg) at Lions Eye Institute, Western Australia from Mar. 2006 to May 2008. All patients received injection at baseline with additional monthly injections given at the discretion of the treating physician. Main outcome measures were changes in VA. RESULTS: There were 371 consecutive patients received injection at least in one eye with at least 6 months of follow up (median of 12.0 months). Bevacizumab treatment prevented 221 out of 278 (79.5%) patient from losing < 15 letters in VA compared with 79 out of 93 (84.9%) of ranibizumab treated patients (P=0.25). While 68 (24.5%) of bevacizumab treated patients gained 15 letters of VA compared with 24 (25.8%) of ranibizumab treated patients (P=0.79). 75.3% and 66.2% patients benefited from ranibizumab and bevacizumab respectively with final VA better than 6/60 (P=0.10). Multivariate analysis showed that pre-treatment VA was negatively associated with benefit outcome. Assignment of injection was not associated with VA outcome of benefit after adjusting the covariate (P=0.857). CONCLUSION: There are no difference in treatment efficacy in terms of VA between bevacizumab and ranibizumab in routine clinical condition.

Bevacizumab vs ranibizumab for neovascular age-related macular degeneration in Chinese patients

AIM: To compare the clinical efficacy of intravitreal injections of bevacizumab and ranibizumab for treating Chinese patients with neovascular age-related macular degeneration (AMD).METHODS: Among 60 Chinese patients with exudative AMD (60 eyes), 28 received intravitreal bevacizumab injections (1.25mg) and 32 received intravitreal ranibizumab injections (0.5mg), once a month for 3 months and were followed for a total of 6 months. Monthly optical coherence tomography (OCT) was used to determine whether the patients received additional treatments during the follow-up. We compared the baseline and 6 -month follow-up values of mean best-corrected visual acuity (BCVA) and central retinal thickness (CRT) in both groups of patients. We also compared the occurrence of adverse events.RESULTS: At the 6-month follow-up, the mean BCVA (logMAR) of the bevacizumab and ranibizumab treatment groups improved from the baseline measurements of 0.72 ±0.23 and 0.73 ±0.22 to 0.47 ±0.14 and 0.45 ±0.20, respectively (P 【0.05 for both groups). However, the change was not significantly different between the two groups. As evaluated by OCT, CRT decreased from 366.71 ±34.72μm and 352 ±36.9μm at baseline to 250.86 ± 41.51μm and 243.22 ±41.38μm in the bevacizumab and ranibizumab groups, respectively (P 【0.05 for both groups). However, the change was not significantly different between the two groups. There were no severe local adverse reactions or systemic adverse events.CONCLUSION:Intravitreal bevacizumab and ranibizumab have equivalent effects on BCVA and CRT and appeare safe over the short-term.

Changes on optical coherence tomography angiography and fluorescein angiography in eyes with neovascular age-related macular degeneration

AIM:lo evaluate the changes on optical coherence tomography angiography(OCTA) and fluorescein angiography(FA) and their correlation in neovascular agerelated macular degeneration(nAMD) before and after intravitreal aflibercept injections(IAIs).METHODS:In 43 treatment-na?ve patients with nAMD,choroidal neovascularization(CNV) in OCTA were morphologically and quantitatively analyzed before and after IAIs to determine whether they are correlated with leakage on FA or not.By combining CNV in OCTA and leakage in FA,lesions were characterized as three types:L+C+(with both CNV and leakage),L-C+(with CNV but without leakage),or L+C-lesion(with leakage outside CNV).RESULTS:Before IAI,while 27 eyes had L+C+lesion only,16 eyes had both L+C+and L-C+lesions simultaneously.Tiny capillaries and anastomosis in CNV were more developed in L+C+lesion,at 86.0% and58.1%,respectively,relative to 9.3% and 9.3% in L-C+lesions(P<0.001).After IAIs in 33 eyes,tiny capillaries and anastomosis were decreased in the lesions with cessation of leakage on FA(P<0.001 and P=0.001,respectively).In quantitative analysis,neovascularization length and numbers of junctions and endpoints were also significantly decreased.CONCLUSION:Leakage on FA is associated with CNV morphology in OCTA and remained so after IAls.Therefore,by carefully assessing the morphological and quantitative changes of CNV in OCTA before and after treatment,activity of nAMD is expected even though CNV on OCTA is not completely matched with fluorescein leakage.

Beta-alanine promotes angiogenesis in laser-induced choroidal neovascularization mice models

AIM:To investigate the effect ofβ-alanine(BA)on laserinduced choroidal neovascularization(CNV)mice models.METHODS:Laser-induced CNV mice models were established,and BA was administrated for one week and two weeks in advance,separately.Furthermore,retinal pigment epithelium(RPE)-choroid flat mounts were separated,and immunohistochemical staining was performed.The laser-induced CNV lesion areas were measured and compared.In addition,liver and kidney morphologies were observed to identify potential hepatorenal toxicity.RESULTS:Enlarged CNV lesion areas were observed in the BA treated group.No significant differences were observed in the liver and kidney sections between groups.CONCLUSION:BA treatment increase CNV lesion areas,suggesting the detrimental effects of BA as a nutritional supplement in age-related macular degeneration(AMD)population.

Recent Developments in the Treatment of Wet Age-related Macular Degeneration

Age-related macular degeneration(AMD)is the most common cause of irreversible blindness and visual impairment in individuals over the age of 50 years in western societies.More than 25 million people currently suffer from this illness in the world,with an additional 500000 every year,approximately.It is a multifactorial ocular disease that affects the maculae due to a late-onset progressive neurodegeneration and dysfunction of photoreceptors and retinal pigment epithelium(RPE).There are many subtypes of AMD but basically two broad forms:the nonneovascular(dry,nonexudative)and neovascular(wet,exudative).Exudative AMD is the less common form(about 15%)but tends to progress more rapidly.At the moment,wet AMD is treated primarily on the basis of anti-vascular endothelial growth factor(VEGF)agents,which have led to massive improvement in the prognosis of the disease since they were first introduced.This article focuses on the latest treatment approaches to neovascular AMD.An extensive literature review was performed in order to illustrate the effectiveness of current and future anti-VEGF agents as well as the landmark clinical studies that have been carried out to establish these drugs as a gold standard in the therapy of wet AMD.

Matrix γ-carboxyglutamate protein and Fetuin-A, in wet type age-related macular degeneration

AIM: To evaluate the high sensitivity C-reactive protein(hs CRP), Fetuin-A and matrix γ-carboxyglutamate protein(MGP) as the main factors for vascular calcification and inflammation in serum of patients with advanced age-related macular degeneration(ARMD) in comparison to healthy controls. METHODS: The subjects were 40 patients with choroidal neovascularization(CNV) having a mean age of70.9 ±9.1y and a matched group of 49 apparently healthy control subjects. The ARMD was diagnosed using a slitlamp with superfield lens, fundus photography and fluorescein angiography. Measurement of hs CRP was done by nephelometry method. Levels of Fetuin-A and MGP were measured by enzyme-linked immunosorbent assay(ELISA) technique.RESULTS: hs CRP [0.45(0.07-2.63) mg/L vs 0.25(0.03-1.2) mg/L, P =0.02)] and Fetuin-A levels(50.27 ±5.04 vs44.99±10.28 ng/m L, P =0.009) were higher in the patients than in the control groups. We could not find significant difference in MGP level between two groups(P =0.08).There was not a significant correlation between MGP with Fetuin-A and hs CRP among the patients(P =0.7, P =0.9respectively). A significant negative correlation of hs CRP with Fetuin-A was observed in both case and control groups(P =0.004, r =-0.33 and P =0.001, r =-0.54,respectively).CONCLUSION: Although our study shows that serum hs CRP and Fetuin-A is increased in CNV patients as well as negatively correlated with both study groups, their direct role on pathogenesis of ARMD required future studies.

A narrative review on the role of abicipar in age-related macular degeneration

In developed countries,age-related macular degeneration(AMD)is the main cause of visual impairment in the elderly.Though the etiology of AMD is still unclear,it has been well understood that vascular endothelial growth factor(VEGF)is involved in the development of aberrant vasculature that represents the neovascular AMD(nAMD).Hence,VEGF inhibition is a more effective way to control nAMD.Pegaptanib,ranibizumab,and aflibercept are three drugs approved by the US Food and Drug Administration(FDA)to treat nAMD.Bevacizumab(an anti-VEGF medication comparable to ranibizumab)is already widely used off label.Existing anti-VEGF medicines are made up of antibodies or pieces of antibodies.Synthetic designed ankyrin repeat proteins(DARPins)imitate antibodies introduced recently by evolutions in bioengineering technology.These agents are designed to have high specificity and affinity to a specific target,smaller molecular size,and better tissue penetration,making them more stable and longer-acting at less concentration.Abicipar pegol(Allergan,Dublin,Ireland)is a DARPin that interlocks all VEGF-A isoforms.It has a greater affinity for VEGF and a longer intraocular half-life than ranibizumab,making it a feasible anti-VEGF agent.This review describes the properties and efficacy of abicipar,the new anti-VEGF agent,in clinical practice,which aims to improve outcomes,safety,and treatment burden of nAMD.

MicroRNAs in laser-induced choroidal neovascularization in mice and rats:their expression and potential therapeutic targets

Choroidal neovascularization characterizes wet age-related macular degeneration.Choroidal neovascularization formation involves a primarily angiogenic process that is combined with both inflammation and proteolysis.A primary cause of choroidal neovascularization pathogenesis is alterations in pro-and anti-angiogenic factors derived from the retinal pigment epithelium,with vascular endothelium growth factor being mainly responsible for both clinical and experimental choroidal neovascularization.MicroRNAs(miRNAs)which are short,non-coding,endogenous RNA molecules have a major role in regulating various pathological processes,including inflammation and angiogenesis.A review of recent studies with the mouse laser-induced choroidal neovascularization model has shown alterations in miRNA expression in choroidal neovascularization tissues and could be potential therapeutic targets for wet age-related macular degeneration.Upregulation of miR-505(days 1 and 3 post-laser),miR-155(day 14)occurred in retina;miR-342-5p(days 3 and 7),miR-126-3p(day 14)in choroid;miR-23a,miR-24,miR-27a(day 7)in retina/choroid;miR-505(days 1 and 3)in retinal pigment epithelium/choroid;downregulation of miR-155(days 1 and 3),miR-29a,miR-29b,miR-29c(day 5),miR-93(day 14),miR-126(day 14)occurred in retinal pigment epithelium/choroid.Therapies using miRNA mimics or inhibitors were found to decrease choroidal neovascularization lesions.Choroidal neovascularization development was reduced by overexpression of miR-155,miR-188-5p,miR-(5,B,7),miR-126-3p,miR-342-5p,miR-93,miR-126,miR-195a-3p,miR-24,miR-21,miR-31,miR-150,and miR-184,or suppression of miR-505,miR-126-3p,miR-155,and miR-23/27.Further studies are warranted to determine miRNA expression in mouse laser-induced choroidal neovascularization models in order to validate and extend the reported findings.Important experimental variables need to be standardized;these include the strain and age of animals,gender,number and position of laser burns to the eye,laser parameters to induce choroidal neovascularization lesions including wavelength,power,spot size,and duration.

Yes-associated protein promotes endothelial-tomesenchymal transition of endothelial cells in choroidal neovascularization fibrosis

AIM:To reveal whether and how Yes-associated protein(YAP)promotes the occurrence of subretinal fibrosis in agerelated macular degeneration(AMD).METHODS:Cobalt chloride(Co Cl2)was used in primary human umbilical vein endothelial cells(HUVECs)to induce hypoxia in vitro.Eight-week-old male C57 BL/6 J mice weighing 19-25 g were used for a choroidal neovascularization(CNV)model induced by laser photocoagulation in vivo.Expression levels of YAP,phosphorylated YAP,mesenchymal markers[αsmooth muscle actin(α-SMA),vimentin,and Snail],and endothelial cell markers(CD31 and zonula occludens 1)were measured by Western blotting,quantitative real-time PCR,and immunofluorescence microscopy.Small molecules YC-1(Lificiguat,a specific inhibitor of hypoxia-inducible factor 1α),CA3(CIL56,an inhibitor of YAP),and XMU-MP-1(an inhibitor of Hippo kinase MST1/2,which activates YAP)were used to explore the underlying mechanism.RESULTS:Co Cl2 increased expression of mesenchymal markers,decreased expression of endothelial cell markers,and enhanced the ability of primary HUVECs to proliferate and migrate.YC-1 suppressed hypoxia-induced endothelialto-mesenchymal transition(End MT).Moreover,hypoxia promoted total expression,inhibited phosphorylation,and enhanced the transcriptional activity of YAP.XMU-MP-1 enhanced hypoxia-induced End MT,whereas CA3 elicited the opposite effect.Expression of YAP,α-SMA,and vimentin were upregulated in the laser-induced CNV model.However,silencing of YAP by vitreous injection of small interfering RNA targeting YAP could reverse these changes.CONCLUSION:The findings reveal a critical role of the hypoxia-inducible factor-1α(HIF-1α)/YAP signaling axis in End MT and provide a new therapeutic target for treatment of subretinal fibrosis in AMD.

A modified laser-induced choroidal neovascularization animal model with intravitreal oxidized low-density lipoprotein

AIM: To investigate whether intravitreal injection of oxidized low-density lipoprotein(OxLDL) can promote laserinduced choroidal neovascularization(CNV) formation in mice and the mechanism involved, thereby to develop a better animal model.METHODS: C57BL6/J mice were randomized into three groups. Immediately after CNV induction with 532 nm laser photocoagulation, 1.0 μL of OxLDL [100 μg/m L in phosphate-buffered saline(PBS)] was intravitreally injected, whereas PBS and the same volume low-density lipoprotein(LDL;100 μg/m L in PBS) were injected into the vitreous as controls. Angiogenic and inflammatory cytokines were measured by quantitative real-time polymerase chain reaction(q RT-PCR) and Western blotting(WB) after 5 d, and CNV severity was analyzed by choroid flat mount and immunofluorescence staining after 1wk. In vitro, retinal pigment epithelial(RPE) cell line(ARPE19) were treated with OxLDL(LDL as control) for 8 h. Angiogenic and inflammatory cytokine levels were measured. A specific inhibitor of lectin-like oxidized low-density lipoprotein receptor 1(LOX1) was used to evaluate the role of LOX1 in this process.RESULTS: At 7 d after intravitreal injection of 1 μL(100 μg/mL) OxLDL, T15-labeled OxLDL was mainly deposited around the CNV area, and the F4/80-labeled macrophages, the CD31-labeled vascular endothelial cells number and CNV area were increased. Meanwhile, WB and qR T-PCR results showed that vascular endothelial growth factor(VEGF), CC chemokine receptor 2(CCR2), interleukin-6(IL-6), IL-1β, and matrix metalloproteinase 9(MMP9) expressions were increased, which was supported by in vitro experiments in RPE cells. LOX1 inhibitors significantly reduced expressions of inflammatory factors IL-1β and VEGF. CONCLUSION: A modified laser-induced CNV animal model is established with intravitreal injection of 1 μL(100 μg/mL) of OxLDL at 7 d, which at least partially through LOX1. This animal model can be used as a simple model for studying the role of OxLDL in age-related macular degeneration.

Effect of flavone on the ocular blood flow and formation of choroidal neovascularization

AIMTo investigate the effect of flavone on ocular blood flow in rabbit eyes and the formation of choroidal neovascularization (CNV) in rat model of age-related macular degeneration (AMD).

Prediction of the short-term efficacy of anti-VEGF therapy for neovascular age-related macular degeneration using optical coherence tomography angiography

Background To evaluate whether the specific choroidal neovascularization(CNV)characteristics measured using optical coherence tomography angiography(OCTA)can predict the 6-month prognosis of neovascular age-related macular degeneration(nAMD)after anti-vascular endothelial growth factor(anti-VEGF)therapy.Methods Patients with type 1,type 2,or mixed-type neovascularization(NV)were prospectively included.Participants underwent an initial loading phase of three consecutive monthly intravitreal injections of Conbercept(0.5 mg)and were switched to a pro re nata(PRN)treatment strategy.OCTA images were evaluated for eyes that underwent follow-up assessments for more than 6 months.CNV lesions were manually segmented,and the CNV area,vessel area,greatest vascular caliber(GVC),and greatest linear dimension(GLD)were compared between responders and non-responders.Two masked graders independently measured the above-mentioned parameters using OCTA,and consistency was assessed using the intraclass correlation coefficient(ICC)values.Multiple logistic regression analysis was performed to evaluate the effect of a 3-month change in the CNV area,GLD,and GVC on the 6-month response to anti-VEGF agents.Results Among the 60 eyes of 60 patients with nAMD,39 were responders and 21 were non-responders.The proportion of CNV types was significantly different between responders and non-responders(P=0.009).Patients with type 2 or mixed NV seemed more likely to respond to the treatment(28.2%vs.0.0%,and 30.8%vs.23.8%,respectively).The change in GVC showed a significant difference between responders(−4.98±17.17μm)and non-responders(11.01±14.10μm)after three monthly intravitreal anti-VEGF injections.Multiple logistic regression analysis showed that only the change in GVC remained significant after controlling for baseline GVC,injection number,and CNV type(adjusted OR=1.083;P=0.008).Conclusions Type 2 and mixed-type NV were significantly associated with a better response to anti-VEGF therapy.Changes in GVC after 3 months of treatment were significantly associated with a response to anti-VEGF therapy at 6 months.

Transcription factor Foxp1 is essential for the induction of choroidal neovascularization

Background The exudative form of age-related macular degeneration(AMD)is characterized by abnormal blood vessel growth,which is stimulated by vascular endothelial growth factor(VEGF)released from retinal pigment epithelium(RPE).The angiogenic behaviors of vascular endothelial cells in vitro depend on forkhead box protein P1(Foxp1),a transcription repressor widely expressed in human and murine tissues during development.In this study,we aimed to determine whether loss of Foxp1 affects laser-induced choroidal neovascularization(CNV)in mouse.Methods Eye-selective deletion of Foxp1 was obtained by crossing Foxp1flox/flox with Six3-Cre mice.Laser photocoagulation was delivered to six-to eight-week-old mice to induce CNV.The expression of Foxp1 and Cre was determined by immunofluorescence in cryostat sections of the eyes.Fundus fluorescein angiography(FFA),optical coherence tomography(OCT),and B4 isolectin staining were applied to analyze the leakage,bulge height,and area of CNV lesions,respectively.RPE-choroid tissues were isolated for the determination of VEGF and pigment epithelium derived factor(PEDF)by Western blotting.Results Foxp1 was expressed in retinal ganglion cells,RPE,and the choroidal endothelial cells.Laser photocoagulation increased the number of Foxp1+-endothelial cells and induced CNV.Six3-Cre reduced Foxp1 expression in RPE but not the endothelium,leading to a lower level of VEGF in the RPE-choroid.Foxp1 knockout inhibited pathological angiogenesis and vascular leakage of the laser-induced CNV lesions.Conclusions Foxp1 regulates the expression of VEGF in the RPE,and inhibition of Foxp1 could potentially be a novel strategy for the prevention and therapy of neovascularization related to AMD.

Diverse roles of macrophages in intraocular neovasculardiseases:a review

Macrophages are involved in angiogenesis, and might also contribute to the pathogenesis of intraocular neovascular diseases. Recent studies indicated that macrophages exert different functions in the process of intraocular neovascularization, and the polarization of M1 and M2 phenotypes plays extremely essential roles in the diverse functions of macrophages. Moreover, a large number of cytokines released by macrophages not only participate in macrophage polarization, but also associate with retinal and choroidal neovascular diseases. Therefore, macrophage might be considered as a novel therapeutic target to the treatment of pathological neovascularization in the eye. This review mainly summarizes diverse roles of macrophages and discusses the possible mechanisms in retinal and choroidal neovascularization.

Comparison of OCT and OCTA manifestations among untreated PCV, neovascular AMD, and CSC in Chinese population

AIM: To compare the qualitative and quantitative features among untreated polypoidal choroidal vasculopathy(PCV), neovascular age-related macular degeneration(nv-AMD) and central serous chorioretinopathy(CSC) using optical coherence tomography(OCT) and OCT angiography(OCTA).METHODS: This retrospective study included 16 eyes with thin-choroid PCV, 18 eyes with thick-choroid PCV, 16 eyes with nv-AMD and 17 eyes with CSC, respectively. The indicators were obtained by OCT and OCTA.RESULTS: Sub-foveal choroidal thickness(SFCT) in CSC was thicker compared to other groups(all P<0.05). SFCT in nv-AMD was thicker compared to thin-choroid PCV, but thinner compared with thick-choroid PCV(both P<0.05). As the ratio of thickness of Haller's layer to thickness of SFCT, which of thin-choroid PCV was significantly higher than CSC(P<0.001). Likewise, thick-choroid PCV had significantly higher ratio than nv-AMD(P=0.016) or CSC(P<0.001). There were differences among them in pigment epithelium detachment(PED). The whole-superficial retinal vessel density(RVD), deep RVD and choroidal capillary vessel density(CCVD) in CSC were significantly higher compared to other three groups, respectively(all P<0.05). The whole CCVD in nv-AMD was higher compared to thick-choroid PCV(P=0.032). Cross-sectional local angiographic form was 87.50%, 83.33%, 0 and 35.29% in thin-choroid PCV, thickchoroid PCV, nv-AMD and CSC, respectively. Cross-sectional diffuse angiographic form was 12.50%, 16.67%, 100% and 5.88% in thin-choroid PCV, thick-choroid PCV, nv-AMD and CSC, respectively.CONCLUSION: Combination of OCT and OCTA can effectively observe the significant alterations existed in PCV, CSC and nv-AMD, and there are distinctive differences among them. The pathogenesis is not exactly the same between PCV and nv-AMD, or PCV and CSC.