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.

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.

Construction and validation of a neovascular glaucoma nomogram in patients with diabetic retinopathy after pars plana vitrectomy

BACKGROUND Neovascular glaucoma(NVG)is likely to occur after pars plana vitrectomy(PPV)for diabetic retinopathy(DR)in some patients,thus reducing the expected benefit.Understanding the risk factors for NVG occurrence and building effective risk prediction models are currently required for clinical research.AIM To develop a visual risk profile model to explore factors influencing DR after surgery.METHODS We retrospectively selected 151 patients with DR undergoing PPV.The patients were divided into the NVG(NVG occurrence)and No-NVG(No NVG occurrence)groups according to the occurrence of NVG within 6 months after surgery.Independent risk factors for postoperative NVG were screened by logistic regression.A nomogram prediction model was established using R software,and the model’s prediction accuracy was verified internally and externally,involving the receiver operator characteristic curve and correction curve.RESULTS After importing the data into a logistic regression model,we concluded that a posterior capsular defect,preoperative vascular endothelial growth factor≥302.90 pg/mL,glycosylated hemoglobin≥9.05%,aqueous fluid interleukin 6(IL-6)≥53.27 pg/mL,and aqueous fluid IL-10≥9.11 pg/mL were independent risk factors for postoperative NVG in patients with DR(P<0.05).A nomogram model was established based on the aforementioned independent risk factors,and a computer simulation repeated sampling method was used to internally and externally verify the nomogram model.The area under the curve(AUC),sensitivity,and specificity of the model were 0.962[95%confidence interval(95%CI):0.932-0.991],91.5%,and 82.3%,respectively.The AUC,sensitivity,and specificity of the external validation were 0.878(95%CI:0.746-0.982),66.7%,and 95.7%,respectively.CONCLUSION A nomogram constructed based on the risk factors for postoperative NVG in patients with DR has a high prediction accuracy.This study can help formulate relevant preventive and treatment measures.

Baerveldt glaucoma implant with Supramid© ripcord stent in neovascular glaucoma: a case series

AIM:To report the outcome of Baerveldt glaucoma implant(BGI)with Supramid©ripcord use in neovascular glaucoma(NVG).METHODS:We retrospectively evaluated the surgical outcome of the BGI with Supramid©3/0 ripcord stent in patients with NVG.No tube ligation or venting slits were performed.Supramid was removed after 3mo if the target intraocular pressure(IOP)was not achieved.Surgical success was defined as IOP≤21 mm Hg with(qualified success)or without IOP-lowering medications(complete success).RESULTS:Twenty-six eyes from 24 patients were included in the study.The median duration of follow-up was 4[interquartile range(IQR)=1-5]y,ranging from 0.5 to 5y.IOP decreased by a mean of 24.2 mm Hg(59.7%);from a mean of 40.5±12.6 mm Hg at baseline to 16.3±11.9 mm Hg,P≤0.001.The number of glaucoma medications reduced from a median of 5(IQR=5-6)to 1(IQR=0-2,P≤0.001)at the final follow-up.Overall success rates were 88.0%at 1y,34.8%at 3y,66.7%at 4y,and 50%at 5y.Hypertensive phase(HP)in the first 3mo occurred in 15/26 eyes(57.7%)with a mean IOP of 31.1 mm Hg.CONCLUSION:BGI with Supramid©ripcord stent gives close to 90%of the overall survival rate at the final follow-up without significant early hypotony.However,early HP is still a challenge.

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.

Etiology, pathogenesis, and diagnosis of neovascular glaucoma

Neovascular glaucoma is defined as iris and/or anterior chamber angle neovascularization associated with increased intraocular pressure. It is a secondary glaucoma that is most frequently caused by severe retinal ischemia. The most common diseases responsible for the development of neovascular glaucoma are diabetic retinopathy, ischemic central retinal vein occlusion,and ocular ischemic syndrome. Uncommon causes include ocular radiation, ocular tumors, uveitis and other miscellaneous conditions. Vascular endothelial growth factor is an important and likely predominant agent involved in the pathogenesis of intraocular neovascularization and neovascular glaucoma. The evolution of clinical and histopathological changes from predisposing conditions to the occurrence of rubeosis iridis and neovascular glaucoma is divided into four stages: prerubeosis, preglaucoma, open angle glaucoma, and angle-closure glaucoma.

A review on vasohibin and ocular neovascularization

Ischemic and neovascular disease is one of the most difficult ocular diseases to deal with nowadays.Redundancy,poor visual acuity and decreased life quality are bothering patients and ophthalmologists for decades.After vascular endothelial growth factor(VEGF)was found to be a primary factor in promoting retinal angiogenesis,intravitreal injection of anti-VEGF drugs has been the firstline treatment.Whereas,some patients are refractory to this therapy and problems of economic burden,local complications and adverse effects promote researches into other possible targets.The vasohibin(VASH)family is a newly-investigated factor in modulating ocular angiogenesis.The family includes VASH1 and VASH2,which show opposite effects of inhibiting and accelerating angiogenesis respectively.Positive results have been reported in cellular and animal experiments.With further researches,it can be a promising future target of treating ocular neovascular diseases.

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.

Assessment of neovascularization within carotid plaques in patients with ischemic stroke

AIM:To assess neovascularization within human ca-rotid atherosclerotic soft plaques in patients with isch-emic stroke.METHODS:Eighty-one patients with ischemic stroke and 95 patients without stroke who had soft athero-sclerotic plaques in the internal carotid artery were studied.The thickest soft plaque in each patient was examined using contrast-enhanced ultrasound.Time-intensity curves were collected from 5 s to 3 min after contrast injection.The neovascularization within the plaques in the internal carotid artery was evaluated using the ACQ software built into the scanner by 2 of the experienced investigators who were blinded to the clinical history of the patients.RESULTS:Ischemic stroke was present in 7 of 33 patients(21%) with grade Ⅰ plaque,in 14 of 51 pa-tients(28%) with grade Ⅱ plaque,in 26 of 43 patients(61%) with grade Ⅲ plaque,and in 34 of 49 patients(69%) with grade Ⅳ plaque(P < 0.001 comparing grade Ⅳ plaque with grade I plaque and with grade Ⅱ plaque and P = 0.001 comparing grade Ⅲ plaque with grade Ⅰ plaque and with grade Ⅱ plaque).Analysis of the time intensity curves revealed that patients with ischemic stroke had a significantly higher intensity of enhancement(IE) than those without ischemic stroke(P < 0.01).The wash-in time(WT) of plaque was signifi-cantly shorter in stroke patients(P < 0.05).The sensi-tivity and specificity for IE in the plaque were 82% and 80%,respectively,and for WT were 68% and 74%,respectively.There was no significant difference in the peak intensity or time to peak between the 2 groups.CONCLUSION:This study shows that the higher the grade of plaque enhancement,the higher the risk of ischemic stroke.The data suggest that the presence of neovascularization is a marker for unstable plaque.

Risk factors associated with retinal neovascularization of diabetic retinopathy in type 2 diabetes mellitus

AIM: To evaluate the risk factors associated with retinal neovascularization of diabetic retinopathy in northern Chinese Han patients with type 2 diabetes mellitus (T2DM). METHODS: The clinical characteristics of 200 patients with proliferative diabetic retinopathy (PDR) and 100 age-matched healthy individuals were compared. The univariate and multivariate logistic regression analysis were performed in the patients with PDR. RESULTS: Fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), blood urea nitrogen (BUN), uric acid (UA), white blood cell count (WBC), absolute neutrophil count, hematocrit (HCT) and mean platelet volume (MPV) and mean platelet volume (MPV) were all significantly higher in patients with PDR than in the control group (P<0.05). The univariate and multivariate logistic regression analysis showed that risk factors independently associated with retinal neovascularization of DR were duration of diabetes mellitus (OR=1.112; P=0.000), BUN (OR=1.277; P=0.000), smoking (OR=3.967; P=0.000) and MPV (OR=2.472; P=0.000). On the other hand, panretinal photocoagulation was associated with reduced risk of retinal neovascularization (OR=0.983; P=0.000). CONCLUSION: Preventing and controlling T2DM in terms of risk factors, including duration of diabetes, BUN, smoking and MPV, might offer novel approaches to prevent or delay the onset of retinal neovascularization in patients with PDR.

Impact of Lycium Barbarum Polysaccharide and Danshensu on vascular endothelial growth factor in the process of retinal neovascularization of rabbit

AIM:To discuss the impact of Lycium Barbarum Polysaccharide (LBP) and Danshensu purified from Traditional Chinese Medicine (TCM) on vascular endothelial growth factor (VEGF) of rabbits with retinal neovascularization. METHODS:Forty rabbits were divided into normal control group, model control group, LBP group and Danshensu group. Animals in the normal control group were fed in the normal oxygen environment. Animals in the other three groups were put into the environment with 70% oxygen for 5 days in order to build the model of oxygen-induced vascular proliferation retinopathy. And then different TCM extract was injected into the abdominal cavities of these annimals. After 7 days, the VEGF content of in the serum of rabbit was measured by double antibody sandwich method. RESULTS:Data analysis indicated that VEGF content was as follows:Danshensu group was lower than model control group (12.92 ±3.84ng/L vs 19.32 ±4.15ng/L, P 【 0.05); LBP group and normal control group were lower than model control group (12.92±3.84ng/L, 9.26±1.61ng/L vs 19.32±4.15ng/L, P【0.01); total blood viscosity, plasma viscosity, cholesterol content, fibrinogen content and triacylglycerol content after peritoneal injection of LBP and Danshensu were obviously lower than before injection. CONCLUSION:TCM extract-LBP and Danshensu can prominently reduce the content of VEGF in the process of vascular proliferative retinopathy of rabbit; can prevent the occurrence of retinal microvascular disease by improving partial oxygen -deficient environment or affecting all kinds of new growth factor.

Growth factor- and cytokine-stimulated endothelial progenitor cells in post-ischemic cerebral neovascularization

Endothelial progenitor cells are resident in the bone marrow blood sinusoids and circulate in the peripheral circulation. They mobilize from the bone marrow after vascular injury and home to the site of injury where they differentiate into endothelial cells. Activation and mobilization of endothelial progenitor cells from the bone marrow is induced via the production and release of endothelial progenitor cell-activating factors and includes specific growth factors and cytokines in response to peripheral tissue hypoxia such as after acute ischemic stroke or trauma. Endotheli- al progenitor cells migrate and home to specific sites following ischemic stroke via growth factor/ cytokine gradients. Some growth factors are less stable under acidic conditions of tissue isch- emia, and synthetic analogues that are stable at low pH may provide a more effective therapeutic approach for inducing endothelial progenitor cell mobilization and promoting cerebral neovascularization following ischemic stroke.

Intravitreal bevacizumab and Ahmed glaucoma valve implantation in patients with neovascular glaucoma

AIM:To explore the efficacy of preoperative intravitreal bevacizumab(IVB) injection combined with Ahmed glaucoma valve(AGV) implantation in the treatment of neovascular glaucoma(NVG).METHODS:This retrospective study included 35 eyes from 35 patients who underwent preoperative IVB and AGV implantation for treatment of NVG. Findings such as intraocular pressure(IOP) number of anti-glaucoma medications, visual acuity(VA), surgical success rates,and complications were recorded.RESULTS:AfterAGVimplantation,IOPwas18.2±4.0mmHg,15.5±3.3 mm Hg and 9.8±2.6 mm Hg at 6, 12 and 36 mo,significantly decreased compared with pre-IOP(P 【0.01).The number of anti-glaucoma medications was 0.9 ±0.5,0.8 ±0.9 and 0.8 ±0.6 at 6, 12 and 36 mo, significantly decreased compared to pre-treatment(P 【0.01). At last visit, there were 19 eyes with stable VA, 4 with VA improvement, 12 with diminished VA and 3 with complete loss light perception. There were 7 cases that failed during 3-year fellow up period. Cumulative probabilities of valve survival by Kaplan-Meier analysis were 82.9%,74.1% and 71.0% at 12, 24 and 36 mo, respectively. Cox stepwise regression analysis found that the survival time was significant associated with the pre-visual acuity 【2/400(P 【0.05). Post-operative complications occurred in 8eyes, of which hyphema presented in 2 eyes, choroidal effusion in 2 eyes.CONCLUSION:The procedure of preoperative IVB andAGV implantation should be one of treatments for NVG because of its safety and effectiveness.

Clinical correlates of common corneal neovascular diseases: a literature review

A large subset of corneal pathologies involves the formation of new vessels(neovascularization), leading to compromised visual acuity. This article aims to review the clinical causes and presentations of corneal neovascularization(CNV) by examining the mechanisms behind common CNV-related corneal pathologies, with a particular focus on herpes simplex stromal keratitis,contact lenses-induced keratitis and CNV secondary to keratoplasty. Moreover, we reviewed CNV in the context of different types of corneal transplantation and keratoprosthesis, and summarized the most relevant treatment available so far.

Comparison of subconjunctivally injected bevacizumab, ranibizumab, and pegaptanib for inhibition of corneal neovascularization in a rat model

AIM: To compare the efficacies of subconjunctival bevacizumab, ranibizumab, and pegaptanib sodium injections for the inhibition of corneal neovascularization in an experimental rat model. METHODS: Sixteen corneas of 16 rats were chemically cauterized and randomized into four groups: bevacizumab group that treated with 0.05mL/1.25mg bevacizumab, ranibizumab group that treated with 0.05mL/0.5mg ranibizumab, pegaptanib group that treated with 0.05mL/0.15mg pegaptanib sodium, and control group that treated with 0.05mL saline solution. Digital photographs of the corneas were taken and analyzed using an image analysis software program. All corneas were excised and examined histologically on the 15 th day. RESULTS: Each treatment group had significantly less neovascularized corneal areas and fewer blood vessels than the control group (all P 【0.05). In addition, bevacizumab group had significantly less neovascu-larized corneal areas and fewer blood vessels than ranibizumab and pegaptanib groups (both P 【0.05). However, there was no significant difference between the ranibizumab and pegaptanib groups regarding percentage of neovascularized corneal areas and number of blood vessels (both P 】0.05). CONCLUSION: Subconjunctival bevacizumab, ranibiz-umab, and pegaptanib sodium were effective with no corneal epitheliopathy for inhibiting corneal neovascularization after corneal burn in rats .Bevacizumab was more effective than ranibizumab and pegaptanib sodium.

Functional expression of a proliferation-related ligand in hepatocellular carcinoma and its implications for neovascularization

AIM： To detect the expression of a proliferation-related ligand on human hepatocellular carcinoma （HCC） cell lines （SK-Hepl, HLE and HepG2） and in culture medium. METHODS： APRIL expression was analyzed by Western blotting in HCC cell lines. Effects of APRIL to cell count and angiogenesis were analyzed, too. RESULTS： Recombinant human APRIL （rhAPRIL） increased cell viability of HepG2 cells and, in HUVEC, rhAPRIL provided slight tolerance to cell death from serum starvation. Soluble APRIL （sAPRIL） from HLE cells increased after serum starvation, but did not change in SK-Hepl or HepG2 cells. These cells showed down-regulation of VEGF after incubation with anti-APRIL antibody. Furthermore, culture medium from the HCC cells treated with anti-APRIL antibody treatment inhibited tube formation of HUVECs. CONCLUSION： Functional expression of APRIL might contribute to neovascularization via an upregulation of VEGF in HCC.

Inhibition of LY294002 in retinal neovascularization via down-regulation the PI3K/AKT-VEGF pathway in vivo and in vitro

AIM： To investigate the effects of the phosphatidylinositol 3-kinase（PI3 K） inhibitor LY294002 on retinal neovascularization（RNV） in the oxygen-induced retinopathy（OIR） mouse model and human umbilical vein endothelial cells（HUVECs）.METHODS： C57 BL/6 J mice were randomly divided into normoxia-control, OIR-control and LY294002 treatment groups. LY294002 or phosphate-buffered solution was intraperitoneally injected daily into mouse pups from P6 to P9 in LY294002 treatment group or OIR-control group. Morphological and pathological changes in RNV, as well as expression levels of PI3 K, serine-threonine kinase（AKT） and vascular endothelial growth factor（VEGF） were observed. HUVECs treating with LY294002 were exposed to hypoxia; the expression of PI3 K, AKT and VEGF were examined by Western blot and RT-PCR analyses.RESULTS： Compared with the OIR-control group, LY294002 significantly inhibit RNV. Adenosine diphosphatase（ADPase） staining and hematoxylin and eosin staining indicated that the clock hour scores of neovascularization and the nuclei of pre-retinal neovascular cells in the LY294002 treatment group were clearly less than those in the OIR-control group（1.41±0.52 vs 6.20±1.21; 10.50±1.58 vs 22.25±1.82, both P〈0.05）. Intravitreal injection of LY294002（in the LY294002 treatment group） markedly decreased PI3 K/AKT-VEGF expression compared with the OIR-control group by immunohistochemistry, Western blotting and RT-PCR（all P〈0.05）. In HUVECs treated with hypoxia, expression of PI3 K, AKT and VEGF were downregulated in the hypoxia-LY294002 group（all P〈0.05）.CONCLUSION： The PI3 K inhibitor LY294002 can inhibit RNV by downregulating PI3 K, AKT, and VEGF expression in vivo and in vitro. LY294002 may provide an effective method for preventing retinopathy of prematurity（ROP）.

Effects of nuclear factor κB expression on retinal neovascularization and apoptosis in a diabetic retinopathy rat model

AIM: To investigate the expression and role of nuclear factor κB(NF-κB) in diabetic retinopathy(DR) and its relationship with neovascularization and retinal cell apoptosis. METHODS: A total of 80 male Wistar rats were randomly assigned to control(4, 8, 12 and 16 wk, n =10 in each group) and diabetes mellitus(DM) groups(4, 8, 12 and 16wk, n =10 in each group). A diabetic rat model was established by intraperitoneal injection of streptozotocin(60 mg/kg). After 4, 8, 12 and 16 wk, rats were sacrificed.Retinal layers and retinal neovascularization growth were stained with hematoxylin-eosin and examined under light microscopy. Cell apoptosis in the retina was detected by Td T-mediated d UTP nick end labeling, and NF-κB distribution and expression in the retina was determined using immunohistochemistry. RESULTS: DM model success rate up to 100%.Diabetes model at each time point after the experimental groupcompared with the control group, the blood glucose was significantly increased, decreased body weight, each time point showed significant differences compared with the control group(P 【0.01). After 12 wk other pathological changes in the retina of diabetic rats were observed; after 16 wk, neovascularization were observed. After 1mo, retinal cell apoptosis was observed.Compared with the control group, NF-κB expression in the DM group significantly increased with disease duration.CONCLUSION: With the prolonging of DM progression,the expression NF-κB increases. NF-κB may be related to retinal cell apoptosis and neovascularization.

Endothelial progenitor cells as factors in neovascularization and endothelial repair

Endothelial progenitor cells(EPCs)are a heterogeneous population of cells that are provided by the bone marrow and other adult tissue in both animals and humans.They express both hematopoietic and endothelial surface markers,which challenge the classic dogma that the presumed differentiation of cells into angioblasts and subsequent endothelial and vascular differentiation occurred exclusively in embryonic development.This breakthrough stimulated research to understand the mechanism(s)underlying their physiologic function to allow development of new therapeutic options.One focus has been on their ability to form new vessels in injured tissues,and another has been on their ability to repair endothelial damage and restore both monolayer integrity and endothelial function in denuded vessels.Moreover,measures of their density have been shown to be a better predictor of cardiovascular events,both in healthy and coronary artery disease populations than the classical tools used in the clinic to evaluate the risk stratification.In the present paper we review the effects of EPCs on revascularization and endothelial repair in animal models and human studies,in an attempt to better understand their function,which may lead to potential advancement in clinical management.