Abnormal Retinal Blood Vessels Research Articles

Photoreceptors inhibit pathological retinal angiogenesis through transcriptional regulation of Adam17 via c-Fos

Pathological retinal angiogenesis profoundly impacts visual function in vascular eye diseases, such as retinopathy of prematurity (ROP) in preterm infants and age-related macular degeneration in the elderly. While the involvement of photoreceptors in these diseases is recognized, the underlying mechanisms remain unclear. This study delved into the pivotal role of photoreceptors in regulating abnormal retinal blood vessel growth using an oxygen-induced retinopathy (OIR) mouse model through the c-Fos/A disintegrin and metalloprotease 17 (Adam17) axis. Our findings revealed a significant induction of c-Fos expression in rod photoreceptors, and c-Fos depletion in these cells inhibited pathological neovascularization and reduced blood vessel leakage in the OIR mouse model. Mechanistically, c-Fos directly regulated the transcription of Adam17 a shedding protease responsible for the production of bioactive molecules involved in inflammation, angiogenesis, and cell adhesion and migration. Furthermore, we demonstrated the therapeutic potential by using an adeno-associated virus carrying a rod photoreceptor-specific short hairpin RNA against c-fos which effectively mitigated abnormal retinal blood vessel overgrowth, restored retinal thickness, and improved electroretinographic (ERG) responses. In conclusion, this study highlights the significance of photoreceptor c-Fos in ROP pathology, offering a novel perspective for the treatment of this disease.

Role of mammalian target of rapamycin in the formation and progression of retinopathy of prematurity-like vascular abnormalities in neonatal rats

Retinopathy of prematurity (ROP), a retinal disease that can occur in premature infants, can lead to severe visual impairment. In this study, we examined the preventive and therapeutic effects of mammalian target of rapamycin complex 1 (mTORC1) inhibition on abnormal retinal blood vessels in a rat model of ROP. To induce ROP-like vascular abnormalities, rats were subcutaneously treated with KRN633, an inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinase, on postnatal day 7 (P7) and P8. KRN633-treated (ROP) rats were treated subcutaneously with the mTORC1 inhibitor rapamycin according to preventive and therapeutic protocols, i.e., from P11 to P13 (P11–P13) and from P14 to P20 (P14–P20), respectively. To compare with the effects of VEGF inhibition, KRN633 was administered according to similar protocols. Changes in retinal vasculature, phosphorylated ribosomal protein S6 (pS6), a downstream indicator of mTORC1 activity, and the proliferative status of vascular cells were evaluated at P14 and P21 using immunohistochemistry. Rapamycin treatment from P11 to P13 prevented increases in arteriolar tortuosity, capillary density, and the number of proliferating vascular cells, and eliminated pS6 immunoreactivity in ROP rats. KRN633 treatment at P11 and P12 (P11/P12) also prevented the appearance of ROP-like retinal blood vessels. Rapamycin treatment from P14 to P20 failed to attenuate arteriolar tortuosity but prevented increases in capillary density and proliferating vascular cell number at the vascular front, but not at the central zone. KRN633 treatment from P14 to P20 significantly reduced abnormalities in the retinal vasculature; however, the effects were inferior to those of KRN633 treatment on P11/P12. These results suggest that activation of the mTORC1 pathway in proliferating endothelial cells contributes to the appearance and progression of ROP-like retinal blood vessels. Therefore, inhibition of mTORC1 may be a promising approach for selectively targeting abnormal retinal blood vessels in ROP.

INCIDENCE AND RISK FACTORS OF RETINOPATHY OF PREMATURITY (ROP): A SINGLE CENTER STUDY IN A TERTIARY CENTER IN INDONESIA

Background: Retinopathy of prematurity (ROP) is an abnormal proliferative retinal blood vessel in premature infants. ROP is known as one of the causes of blindness in children in developed countries. Objectives: We conducted this study to report the incidence and identify the potential risk factors associated with ROP. Methods: This study was a hospital-based retrospective cohort study of preterm infants in the tertiary neonatal intensive care unit from May 2009 to April 2011. The ROP was identified by an ophthalmologist with binocular indirect ophthalmoscope (BIO). Potential risk factors such as gestational age, birth weight, oxygen therapy, sepsis, small for gestational age, blood transfusion, asphyxia, and respiratory distress syndrome were analyzed using the bivariate and multivariate analysis. Results: There were 248 preterm infants enrolled in this study. Thirty-two (12.9%) patients were diagnosed with various ROP stages, and 43.7% patients suffer from severe ROP requiring treatment for severe ROP. Gestational age and birth weight were not independent risk factors of ROP. In contrast, oxygen therapy (OR 36.93, CI 4.73-288.02), sepsis (OR 4.86, CI 1.85-12.82), and small for gestational age (OR 3.99, CI 1.47-10.82) include as independent risk factors. Conclusions: Incidence of ROP were 12.9%, while the independent risk factors were oxygen therapy, sepsis, and small for gestational age.

Changes in components of the neurovascular unit in the retina in a rat model of retinopathy of prematurity.

An impairment of cellular interactions between the elements of the neurovascular unit contributes to the onset and/or progression of retinal diseases. The present study aims to examine how elements of the neurovascular unit are altered in a rat model of retinopathy of prematurity (ROP). Neonatal rats were treated subcutaneously with the vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor KRN633 (10mg/kg) on postnatal day (P) 7 and P8 to induce ROP. Morphological assessments were performed of blood vessels, astrocytes and neuronal cells in the retina. Aggressive angiogenesis, tortuous arteries and enlarged veins were observed in the retinal vasculature of KRN633-treated (ROP) rats from P14 to P28, compared to age-matched control (vehicle-treated) animals. Morphological abnormalities in the retinal vasculature showed a tendency toward spontaneous recovery from P28 to P35 in ROP rats. Immunofluorescence staining for glial fibrillary acidic protein and Pax2 (astrocyte markers) revealed that morphological changes to and a reduction in the number of astrocytes occurred in ROP rats. The developmental cell death was slightly accelerated in ROP rats; however, no visible changes in the morphology of retinal layers were observed on P35. The abnormalities in astrocytes might contribute, at least in part, to the formation of abnormal retinal blood vessels and the pathogenesis of ROP.

Image Processing for the Detection of Diabetic Retinopathy and Diabetic Macular Edema

Diabetic retinopathy (DR) and diabetic macular edema (DME) are common microvascular retinal diseases in patients with diabetes. The diabetic patients may have a sudden and devastating impact on visual acuity, in the long run leading to blindness. Advanced stages of DR are characterized by the growth of abnormal retinal blood vessels secondary to ischemia. These blood vessels grow in an attempt to supply oxygenated blood to the hypoxic retina. At any time during the progression of DR, patients with diabetes can also develop DME, which involves retinal thickening in the macular area. In the present paper, algorithms are developed to detect DR and DME. For detecting DR the abnormalities in the retina blood vessels are detected by classifying the common abnormalities namely microaneurisms, hard exudates, heammorages and cotton wool spots. DME is detected by finding the nearness of Hard exudate to macula. The macula and hard exudates are localized using image processing techniques. Severity of DME is assessed based on the nearest exudates, their area and color analysis. The algorithm is tested with 65 DR and DME images with severity index 0, 1 and 2 from MESSIDOR database.

Successful resolution of coats disease by photodynamic therapy: a case report

BackgroundCoats disease is a retinal disease characterized by exudative retinal detachment due to abnormal retinal blood vessels. Coats disease is generally treated using laser photocoagulation and cryotherapy to ablate the abnormal retinal blood vessels. However, if abnormal blood vessels are present near the posterior pole of the eye and there is a severe exudative change there, it is difficult to perform these standard treatments. We describe a case of Coats disease with severe exudative retinal change and retinal vascular abnormality near the posterior pole for which we performed photodynamic therapy and successfully suppressed the disease and improved vision.Case presentationA 15-year-old Japanese boy presented to hospital with a chief complaint of decreased vision in his right eye. At the initial examination, corrected visual acuity of the right eye was 20/100. On the right fundus, exudative retinal detachment with subretinal haemorrhage was observed from the upper intermediate periphery to the posterior pole. Abnormal telangiectatic vessels and microaneurysms were found at the nasal peripheral retina. From these findings, we diagnosed the case as Coats disease. We conducted photodynamic therapy for the right eye. At 10 months after treatment, both the subretinal haemorrhage and the exudative retinal detachment had disappeared completely. Further, the retinal structure of the macula had recovered, and right vision had improved to 20/20.ConclusionPhotodynamic therapy may be an effective and safe treatment for Coats disease in cases that present with abnormal retinal vessels close to the posterior pole of the eye.

Retinal neuronal cell loss prevents abnormal retinal vascular growth in a rat model of retinopathy of prematurity

A short-term blockade of the vascular endothelial growth factor (VEGF)-mediated pathway in neonatal rats results in formation of severe retinopathy of prematurity (ROP)-like retinal blood vessels. The present study aimed to examine the role of retinal neurons in the formation of abnormal retinal blood vessels. Newborn rats were treated subcutaneously with the VEGF receptor tyrosine kinase inhibitor, KRN633 (10 mg/kg), or its vehicle (0.5% methylcellulose in water) on postnatal day (P) 7 and P8. To induce excitotoxic loss of retinal neurons, N-methyl-D-aspartic acid (NMDA) was injected into the vitreous chamber of the eye on P9. Changes in retinal morphology, blood vessels, and proliferative status of vascular cells were evaluated on P11 and P14. The number of cells in the ganglion cell layer and the thickness of the inner plexiform layer and inner nuclear layer were significantly decreased 2 days (P11) after NMDA treatment. The pattern and degree of NMDA-induced changes in retinal morphology were similar between vehicle-treated (control) and KRN633-treated (ROP) rats. In ROP rats, increases in the density of capillaries, the tortuosity index of arteries, and the proliferating vascular cells were observed on P14. The expansion of the endothelial cell network was prevented, and the capillary density and the number of proliferating cells were reduced in NMDA-treated retinas of both control and ROP rats. Following NMDA-induced neuronal cell loss, no ROP-like blood vessels were observed in the retinas. These results suggest that retinal neurons play an important role in the formation of normal and ROP-like retinal blood vessels.

Hot Topics in Retinopathy of Prematurity.

Retinopathy of prematurity (ROP) is a condition seen in premature infants that is characterized by abnormal retinal blood vessel growth incited by relative hyperoxia and followed by hypoxia. It can have severe consequences ranging from high myopia to blindness. This article reviews recent "hot" topics related to ROP, specifically the changing incidence of ROP worldwide, the advent of predictive algorithms for screening for ROP, the emerging data behind efficacy of anti-vascular endothelial growth factor treatments for ROP, and advanced retinal imaging in children who were born premature. [Pediatr Ann. 2017;46(11):e415-e422.].

Implementation of Stochastic Approach for Vessel and Ridge Studies in Retinopathy of Prematurity Screening

The retinopathy of prematurity (ROP) is an ocular pathological disorder of retinal blood vessels in premature infants and low birth weight infants. The medical professional who is taking care of premature infants should know who is at the risk of this disease and its exact severity stage. It is also important to decide when screening must begin and how often these infants need to be examined as disease progression leads to a more severe stage causing blindness. The contrast stretching method has been utilized to enhance the ROP colour image. Then an automatic isotropic undecimated wavelet transform (IUWT) scheme has been proposed to extract the abnormal retinal blood vessel and measure its width and tortuosity. The ridge formation of this pathological disorder has also been extracted by IUWT. The quantitative measurements of mean diameter, standard deviation, tortuosity, length of retinal blood vessel and ridge have been considered and computed to find the exact severity stage of ROP. The proposed methods for ROP stage screening system have been validated through machine vision techniques. This proposed system improves the optimum time utilization for ophthalmologists; ophthalmic technicians can provide exact ROP stage and deliver better accuracy and sensitivity in diagnosis.

Inhibition of high glucose‐induced diabetic retinal angiogenesis by dietary compound chrysin

Diabetic retinopathy (DR) has been implicated in patients suffering from chronic diabetes mellitus as pathological complications, characterized by diabetic retinal edema and abnormal retinal blood vessel outgrowth leading to diabetic vision loss. Chrysin is a natural flavonoid found in herb and honeycomb and possesses various bioactive properties. This study investigated to determine protective effects of chrysin on retinal angiogenesis caused by diabetic episode. Human retinal microvascular endothelial cells were incubated in media containing 27.5 mM mannitol (+5.5 mM glucose) or 33 mM glucose for 2 d in the presence of non‐toxic chrysin at 1–20 μM. High glucose upregulated the induction of the angiogenic markers of hypoxia inducible factor (HIF)‐1α and vascular endothelial growth factor (VEGF). In contrast, chrysin attenuated the induction of these angiogenic marker proteins. In the in vivo animal model of db/db mice, oral administration of 10 mg/kg chrysin decreased the retinal induction of HIF‐1α and VEGF and blocked retinal edema in db/db mice. These result demonstrated that chrysin inhibited retinal angiogenesis and edema retinal by attenuating the induction of angiogenic factors under diabetic circumstances. Therefore, chrysin may be a therapeutic agent in antagonizing diabetic retinopathy.Support or Funding InformationThis study was supported by National Research Foundation of Korea (2015R1A2A2A01006666) and Brain Korea 21 plus program by Ministry of Education of Korea (22A20130012421).

Short-term treatment with VEGF receptor inhibitors induces retinopathy of prematurity-like abnormal vascular growth in neonatal rats

Retinal arterial tortuosity and venous dilation are hallmarks of plus disease, which is a severe form of retinopathy of prematurity (ROP). In this study, we examined whether short-term interruption of vascular endothelial growth factor (VEGF) signals leads to the formation of severe ROP-like abnormal retinal blood vessels. Neonatal rats were treated subcutaneously with the VEGF receptor (VEGFR) tyrosine kinase inhibitors, KRN633 (1, 5, or 10 mg/kg) or axitinib (10 mg/kg), on postnatal day (P) 7 and P8. The retinal vasculatures were examined on P9, P14, or P21 in retinal whole-mounts stained with an endothelial cell marker. Prevention of vascular growth and regression of some preformed capillaries were observed on P9 in retinas of rats treated with KRN633. However, on P14 and P21, density of capillaries, tortuosity index of arterioles, and diameter of veins significantly increased in KRN633-treated rats, compared to vehicle (0.5% methylcellulose)-treated animals. Similar observations were made with axitinib-treated rats. Expressions of VEGF and VEGFR-2 were enhanced on P14 in KRN633-treated rat retinas. The second round of KRN633 treatment on P11 and P12 completely blocked abnormal retinal vascular growth on P14, but thereafter induced ROP-like abnormal retinal blood vessels by P21. These results suggest that an interruption of normal retinal vascular development in neonatal rats as a result of short-term VEGFR inhibition causes severe ROP-like abnormal retinal vascular growth in a VEGF-dependent manner. Rats treated postnatally with VEGFR inhibitors could serve as an animal model for studying the mechanisms underlying the development of plus disease.

Gene therapy for age-related macular degeneration

Age-related macular degeneration is the most common cause of untreatable blindness in the world, and its prevalence is increasing. 1 Bourne RR Stevens GA White RA et al. Causes of vision loss worldwide, 1990–2010: a systematic analysis. Lancet Glob Health. 2013; 1: e339-e349 Summary Full Text Full Text PDF PubMed Scopus (1034) Google Scholar Current therapies for neovascular age-related macular degeneration aim to prevent growth of the abnormal retinal blood vessels that could leak and cause rapid visual loss in the later stages of the disease. This growth inhibition is achieved by regular injections into the eye of molecules that block the activity of vascular-endothelial growth factor (VEGF). 2 Schmidt-Erfurth U Chong V Loewenstein A et al. Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA). Br J Ophthalmol. 2014; 98: 1144-1167 Crossref PubMed Scopus (358) Google Scholar These drugs are expensive, and the requirement for regular and indefinite intraocular injections puts a substantial strain on health-care resources. In The Lancet, Elizabeth Rakoczy and colleagues 3 Rakoczy EP Lai C-M Magno AL et al. Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial. Lancet. 2015; (published online Sept 30.)http://dx.doi.org/10.1016/S0140-6736(15)00345-1 PubMed Google Scholar present 1 year results from a phase 1 clinical trial to assess a single treatment, with gene therapy, as an alternative to regular injections for achieving long-term VEGF blockade. 3 Rakoczy EP Lai C-M Magno AL et al. Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial. Lancet. 2015; (published online Sept 30.)http://dx.doi.org/10.1016/S0140-6736(15)00345-1 PubMed Google Scholar Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trialrAAV.sFLT-1 was safe and well tolerated. These results support ocular gene therapy as a potential long-term treatment option for wet age-related macular degeneration. Full-Text PDF

Commentary: "prom1 function in development, intestinal inflammation, and intestinal tumorigenesis".

Commentary: "prom1 function in development, intestinal inflammation, and intestinal tumorigenesis".

Surgical Management of Diabetic Macular Edema.

Diabetic macular edema (DME) is typically caused by leakage from abnormal retinal blood vessels. Mechanical causes at the vitreoretinal interface are increasingly implicated in select patients. Surgical interventions, including vitrectomy, epiretinal membrane (ERM) peel, and internal limiting membrane (ILM) peel, have been proposed in these patients to relieve traction, clear cytokines, and improve oxygenation. This chapter reviews the efficacy of these interventions, which varies by the type of vitreoretinal interface abnormality. Vitrectomy is beneficial in most DME cases where a taut posterior hyaloid or vitreomacular traction is present. It can also be beneficial in select cases where the posterior hyaloid is attached, even if there is no observable traction. When separation of the posterior hyaloid has occurred, vitrectomy can still be beneficial if an ERM is present. Unfortunately, favorable anatomic results, including improved thickness on optical coherence topography scans, are more common than improved visual results. This may reflect that surgical intervention is often performed for refractory DME cases with long-standing edema, with limited potential for substantial improvement. However, surgical intervention may be beneficial for select cases of DME, especially when surgical intervention is undertaken before photoreceptor damage has occurred.

Retinopathy of Prematurity Vessel and Ridge Parameters Measurement by Unsupervised Algorithm

The Retinopathy of Prematurity (ROP) is an ocular pathological disorder of the retinal blood vessels in premature infants and low birth weight infants. It is essential that those caring for premature infants should know who is at risk of ROP and their severity stage. It is also important that when screening must begin and how often these infants need to be examined otherwise the progression lead most severe stage and can cause blindness. The contrast stretching method has been utilized to enhance the ROP color image. Then an automatic method Isotropic Un-decimated Wavelet Transform (IUWT) has been proposed to extract the abnormal retinal blood vessel and measure its width and tortuosity. The ridge formation of this pathological disorder has also been obtained by the IUWT. The quantitative measurements of mean diameter, standard deviation, tortuosity, length of retinal blood vessel and ridge have been considered and computed the exact severity stage of ROP. The effectiveness of the proposed method has been verified through machine vision techniques and the results obtained are encouraged by experts. Automatic ROP screening system comprises several advantages, like a substantial time reduction of ophthalmologists in diagnosis, a non ophthalmologist can provide stage of ROP, improving the sensitivity of the test and a better accuracy in diagnosis.

Alterations of the tunica vasculosa lentis in the rat model of retinopathy of prematurity

To study the relationship between retinal and tunica vasculosa lentis (TVL) disease in retinopathy of prematurity (ROP). Although the clinical hallmark of ROP is abnormal retinal blood vessels, the vessels of the anterior segment, including the TVL, are also altered. ROP was induced in Long-Evans pigmented and Sprague Dawley albino rats; room-air-reared (RAR) rats served as controls. Then, fluorescein angiographic images of the TVL and retinal vessels were serially obtained with a scanning laser ophthalmoscope near the height of retinal vascular disease, ~20days of age, and again at 30 and 64days of age. Additionally, electroretinograms (ERGs) were obtained prior to the first imaging session. The TVL images were analyzed for percent coverage of the posterior lens. The tortuosity of the retinal arterioles was determined using Retinal Image multiScale Analysis (Gelman et al. in Invest Ophthalmol Vis Sci 46:4734-4738, 2005). In the youngest ROP rats, the TVL was dense, while in RAR rats, it was relatively sparse. By 30days, the TVL in RAR rats had almost fully regressed, while in ROP rats, it was still pronounced. By the final test age, the TVL had completely regressed in both ROP and RAR rats. In parallel, the tortuous retinal arterioles in ROP rats resolved with increasing age. ERG components indicating postreceptoral dysfunction, the b-wave, and oscillatory potentials were attenuated in ROP rats. These findings underscore the retinal vascular abnormalities and, for the first time, show abnormal anterior segment vasculature in the rat model of ROP. There is delayed regression of the TVL in the rat model of ROP. This demonstrates that ROP is a disease of the whole eye.

Diabetic Retinopathy and Angiogenesis

Diabetic retinopathy, a secondary microvascular complication of diabetes mellitus is the leading cause of blindness in the Unites States amongst individuals age 20 to 64. Two major retinal problems cause most of the diabetes-related vision loss: diabetic macular edema and complications from abnormal retinal blood vessel growth, angiogenesis. Secondary to angiogenesis, increased retinal blood flow is of pathogenic importance in the progression of diabetic retinopathy. Understanding the role of hyperglycemia seems to be the most critical factor in regulating retinal blood flow, as increased levels of blood glucose are thought to have a structural and physiological effect on retinal capillaries causing them to be both functionally and anatomically incompetent. High blood glucose induces hypoxia in retinal tissues, thus leading to the production of VEGF-A (vascular endothelial growth factor protein). Hypoxia is a key regulator of VEGF-induced ocular neovascularization. Secondary to the induction of VEGF by hypoxia, angiogenesis can be controlled by angiogenic inducers and inhibitors. The balance between VEGF and angiogenic inhibitors may determine the proliferation of angiogenesis in diabetic retinopathy. Since VEGF-A is a powerful angiogenic inducer, utilizing anti-VEGF treatments has proved to be a successful protocol in the treatment of proliferative diabetic retinopathy.

Tubedown associates with cortactin and controls permeability of retinal endothelial cells to albumin

Tubedown (Narg1, Tbdn), a member of the Nat1 family of proteins, associates with the acetyltransferase Ard1 and exerts an angiostatic function in adult retinal-blood-vessel homeostasis. The purpose of the present study was to gain a better understanding of the nature of the Tbdn protein complex and how it might exert a homeostatic influence on blood vessels. Immunoprecipitation of Tbdn from endothelial cells followed by gel electrophoresis and liquid-chromatography-tandem-mass-spectrometry identified the actin-cytoskeleton-binding protein cortactin as a co-immunopurifying species. Western blotting confirmed the association between Tbdn and cortactin. Immunofluorescence confocal microscopy revealed that Tbdn colocalizes with cortactin and F-actin in cytoplasmic regions and at the cortex of cultured endothelial cells. Because cortactin is known to regulate cellular permeability through its interaction with the actin cytoskeleton, a process that is crucial for endothelial cell homeostasis, the role of Tbdn on endothelial cell permeability was examined. Knockdown of Tbdn expression in endothelial cells led to the co-suppression of Ard1 protein expression and to a significant increase in cellular permeability measured by the transit of FITC-albumin across the cellular monolayer. Furthermore, the proliferative retinal neovascularization and thickening resulting from induction of Tbdn knockdown in endothelium in transgenic mice was associated with a significant increase in extravasation or leakage of albumin from abnormal retinal blood vessels in vivo. These results provide evidence that an association occurs between Tbdn and cortactin, and that Tbdn is involved in the regulation of retinal-endothelial-cell permeability to albumin. This work implicates a functional role for Tbdn in blood-vessel permeability dynamics that are crucial for vascular homeostasis.