Retinopathy Of Prematurity Model Research Articles

Assessment of the G-ROP study criteria for predicting retinopathy of prematurity: results from a tertiary centre in Turkey.

The postnatal growth and retinopathy of prematurity (G-ROP) study has proposed a new model for retinopathy of prematurity (ROP) prediction based on gestational age, birth weight and postnatal weight gain. The purpose of the current study is to assess the efficacy of the G-ROP modelfor predicting ROP among a Turkish cohort of premature infants. Records of infants who underwent ROP screening examinations between 2012 and 2019 were reviewed retrospectively. Infants with a documented ROP outcome and regular body weight measurements until day 40 of life were included. The G-ROP model was applied to the study group. The outcome measures were sensitivity and specificity of the model for detecting any stage ROP and treated ROP. A total of 242 infants were included. The G-ROP model identified 168 infants to be screened for ROP. The sensitivity was 88.3% for detecting any stage ROP and 91.2% for treated ROP. The specificity for any stage ROP and treated ROP was 51.7% and 34.1%, respectively. The incorporation of bronchopulmonary dysplasia to the model increased the sensitivity to 100% with 22.7% reduction in the number of screened infants. The G-ROP model is a simple and effective method for ROP prediction. However, in the current cohort, a small number of infants requiring treatment would be missed if G-ROP criteria were applied. The model may be modified with addition of bronchopulmonary dysplasia to detect all treatment requiring cases. Prospective studies among larger groups are necessary to assess the applicability of the modified model.

Retinal plasticity in retinopathy of prematurity, and phototherapy prospects

In premature babies, plastic changes develop in the neural retina, which, depending on the severity of retinopathy of prematurity (ROP), are a manifestation of adaptive or non-adaptive plasticity. In various experimental studies on animal ROP models, the conditioning effects of intermittent white light stimulation and various mechanisms of the positive effect of red and ultraviolet radiation on the plasticity of the retina have been demonstrated, which allows phototherapy to be considered as a promising modifying treatment for ROP supplementing the main therapy. Taking into account that light-dependent processes are involved in the pathogenesis of ROP, we also hypothesize that fractal phototherapy with complex-structured optical stimuli, as a method of activating adaptive neuroplasticity, can be most effective in the complex of methods for preventing and treating ROP.

Novel Anti-Interleukin-1β Therapy Preserves Retinal Integrity: A Longitudinal Investigation Using OCT Imaging and Automated Retinal Segmentation in Small Rodents.

Retinopathy of prematurity (ROP) is the leading cause of blindness in neonates. Inflammation, in particular interleukin-1β (IL-1β), is increased in early stages of the disorder, and contributes to inner and outer retinal vasoobliteration in the oxygen-induced retinopathy (OIR) model of ROP. A small peptide antagonist of IL-1 receptor, composed of the amino acid sequence, rytvela, has been shown to exert beneficial anti-inflammatory effects without compromising immunovigilance-related NF-κB in reproductive tissues. We conducted a longitudinal study to determine the efficacy of “rytvela” in preserving the integrity of the retina in OIR model, using optical coherence tomography (OCT) which provides high-resolution cross-sectional imaging of ocular structures in vivo. Sprague–Dawley rats subjected to OIR and treated or not with “rytvela” were compared to IL-1 receptor antagonist (Kineret). OCT imaging and custom automated segmentation algorithm used to measure retinal thickness (RT) were obtained at P14 and P30; gold-standard immunohistochemistry (IHC) was used to confirm retinal anatomical changes. OCT revealed significant retinal thinning in untreated animals by P30, confirmed by IHC; these changes were coherently associated with increased apoptosis. Both rytvela and Kineret subsided apoptosis and preserved RT. As anticipated, Kineret diminished both SAPK/JNK and NF-κB axes, whereas rytvela selectively abated the former which resulted in preserved monocyte phagocytic function. Altogether, OCT imaging with automated segmentation is a reliable non-invasive approach to study longitudinally retinal pathology in small animal models of retinopathy.

Expression profiles of long noncoding RNAs in retinopathy of prematurity.

Long noncoding RNA (lncRNA) regulates the proliferation and migration of human retinal endothelial cells, as well as retinal neovascularization in diabetic retinopathy. Based on similarities between the pathogenesis of retinopathy of prematurity (ROP) and diabetic retinopathy, lncRNA may also play a role in ROP. Seven-day-old mice were administered 75 ± 2% oxygen for 5 days and normoxic air for another 5 days to establish a ROP model. Expression of lncRNA and mRNA in the retinal tissue of mice was detected by high-throughput sequencing technology, and biological functions of the resulted differentially expressed RNAs were evaluated by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. The results showed that compared with the control group, 57 lncRNAs were differentially expressed, including 43 upregulated and 14 downregulated, in the retinal tissue of ROP mice. Compared with control mice, 42 mRNAs were differentially expressed in the retinal tissue of ROP mice, including 24 upregulated and 18 downregulated mRNAs. Differentially expressed genes were involved in ocular development and related metabolic pathways. The differentially expressed lncRNAs may regulate ROP in mice via microRNAs and multiple signaling pathways. Our results revealed that these differentially expressed lncRNAs may be therapeutic targets for ROP treatment. This study was approved by the Medical Ethics Committee of Shengjing Hospital of China Medical University on February 25, 2016 (approval No. 2016PS074K).

Changes in the expression of autophagy markers in a rat model of retinopathy of prematurity

AbstractPurposeAutophagy is an essential process in maintaining the normal cellular homeostasis and energy balance under physiological conditions. In retinal diseases, autophagy helps retinal cells defend themselves against harmful stress; however, excessive autophagy may result in retinal deterioration. Modulating autophagy may provide an alternative therapeutic strategy to treat retinal diseases. Retinopathy of prematurity (ROP) is a human vascular disease characterized by the formation of neovascularization in the premature newborn retina. There is only limited information on the role of autophagy in ROP.MethodsA rat model of oxygen‐induced retinopathy (OIR), an acknowledged model of ROP, was used to evaluate changes in the expression of key mediators of autophagy induced by the disease. In this model, rat pups are exposed to alternating cycles of 50% and 10% oxygen for 24‐h for the first 14 days followed by exposure to the room air until post‐natal day 18. The expression of autophagy markers from birth to post‐natal day 18 was assessed at transcript and protein levels by real‐time PCR and Western blot, respectively. In addition, the phosphorylation status of signaling molecules known to activate or to repress autophagy was investigated.ResultsIn control rats, the autophagic flux decreased over time during post‐natal development. In contrast, in OIR rats the levels of autophagic markers transiently increased at post‐natal day 7 to then gradually decrease until post‐natal day 18.ConclusionsThe present findings sustain the role of dysregulated autophagic processes in the pathogenesis of ROP and point to the targeting of autophagy as a potential treatment for neovascular eye diseases.

A Prediction Model for Retinopathy of Prematurity—Is It Ready for Prime Time?

A Prediction Model for Retinopathy of Prematurity—Is It Ready for Prime Time?

Regionally Specific Economic Impact of Screening and Treating Retinopathy of Prematurity in Middle-Income Societies in the Philippines

To estimate the economic effects of implementing a universal screening and treatment program for retinopathy of prematurity (ROP) in the Philippines with the Economic Model for Retinopathy of Prematurity (EcROP). The EcROP is a cost-effectiveness, cost-benefit, and cost-utility analysis. Fifty parents of legally blind individuals (aged 3 to 28 years) from three schools for the blind in the Philippines were interviewed to estimate the societal burden of raising a blind child. A decision tree analytic model, with deterministic and probabilistic sensitivity analysis, was used to calculate the incremental cost-effectiveness ratio (primary outcome) and the incremental monetary benefit (secondary outcome) for implementing an optimal national ROP program, compared to estimates of the current policy. Findings were extrapolated to estimate the national economic benefit of an ideal screening and treatment program. The incremental cost-effectiveness ratio for a national program over the current policy was strongly favorable to the ideal program for the Philippines and represents an opportunity for substantial societal cost savings. The per-child incremental, annual monetary benefit of a national program over the current policy was $2,627. Extrapolating to the population of children at risk in 1 year showed that the national annual net benefit estimate would be $64,320,692, which is favorable to the current policy. The EcROP demonstrates that implementing a national ROP screening and treatment program is cost-saving and cost-effective, and would substantially decrease childhood blindness in the Philippines. [J Pediatr Ophthalmol Strabismus. 2019;56(6):388-396.].

Progenitor cell combination normalizes retinal vascular development in the oxygen-induced retinopathy (OIR) model

Retinopathy of prematurity (ROP) is a disorder of the developing retina of preterm infants. ROP can lead to blindness because of abnormal angiogenesis that is the result of suspended vascular development and vaso-obliteration leading to severe retinal stress and hypoxia. We tested the hypothesis that the use of the human progenitor cell combination, bone marrow-derived CD34+ cells and vascular wall-derived endothelial colony-forming cells (ECFCs), would synergistically protect the developing retinal vasculature in a mouse model of ROP, called oxygen-induced retinopathy (OIR). CD34+ cells alone, ECFCs alone, or the combination thereof were injected intravitreally at either P5 or P12 and pups were euthanized at P17. Retinas from OIR mice injected with ECFCs or the combined treatment revealed formation of the deep vascular plexus (DVP) while still in hyperoxia, with normal-appearing connections between the superficial vascular plexus (SVP) and the DVP. In addition, the combination of cells completely prevented aberrant retinal neovascularization and was more effective anatomically and functionally at rescuing the ischemia phenotype than either cell type alone. We show that the beneficial effects of the cell combination are the result of their ability to orchestrate an acceleration of vascular development and more rapid ensheathment of pericytes on the developing vessels. Lastly, our proteomic and transcriptomic data sets reveal pathways altered by the dual cell therapy, including many involved in neuroretinal maintenance, and principal component analysis (PCA) showed that cell therapy restored OIR retinas to a state that was closely associated with age-matched normal retinas. Together, these data herein support the use of dual cell therapy as a promising preventive treatment for the development of ROP in premature infants.

Soluble epoxide hydrolase promotes astrocyte survival in retinopathy of prematurity.

Polyunsaturated fatty acids such as docosahexaenoic acid (DHA) positively affect the outcome of retinopathy of prematurity (ROP). Given that DHA metabolism by cytochrome P450 and soluble epoxide hydrolase (sEH) enzymes affects retinal angiogenesis and vascular stability, we investigated the role of sEH in a mouse model of ROP. In WT mice, hyperoxia elicited tyrosine nitration and inhibition of sEH and decreased generation of the DHA-derived diol 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP). Correspondingly, in a murine model of ROP, sEH-/- mice developed a larger central avascular zone and peripheral pathological vascular tuft formation than did their WT littermates. Astrocytes were the cells most affected by sEH deletion, and hyperoxia increased astrocyte apoptosis. In rescue experiments, 19,20-DHDP prevented astrocyte loss by targeting the mitochondrial membrane to prevent the hyperoxia-induced dissociation of presenilin-1 and presenilin-1-associated protein to attenuate poly ADP-ribose polymerase activation and mitochondrial DNA damage. Therapeutic intravitreal administration of 19,20-DHDP not only suppressed astrocyte loss, but also reduced pathological vascular tuft formation in sEH-/- mice. Our data indicate that sEH activity is required for mitochondrial integrity and retinal astrocyte survival in ROP. Moreover, 19,20-DHDP may be more effective than DHA as a nutritional supplement for preventing retinopathy in preterm infants.

A Small-Molecule Pan-Id Antagonist Inhibits Pathologic Ocular Neovascularization

SUMMARYId helix-loop-helix (HLH) proteins (Id1–4) bind E protein bHLH transcription factors, preventing them from forming active transcription complexes that drive changes in cell states. Id proteins are primarily expressed during development to inhibit differentiation, but they become re-expressed in adult tissues in diseases of the vasculature and cancer. We show that the genetic loss of Id1/Id3 reduces ocular neovascularization in mouse models of wet age-related macular degeneration (AMD) and retinopathy of prematurity (ROP). An in silico screen identifies AGX51, a small-molecule Id antagonist. AGX51 inhibits the Id1-E47 interaction, leading to ubiquitin-mediated degradation of Ids, cell growth arrest, and reduced viability. AGX51 is well-tolerated in mice and phenocopies the genetic loss of Id expression in AMD and ROP models by inhibiting retinal neovascularization. Thus, AGX51 is a first-in-class compound that antagonizes an interaction formerly considered undruggable and that may have utility in the management of multiple diseases.

The Inability of the Choroid to Revascularize in Oxygen-Induced Retinopathy Results from Increased p53/miR-Let-7b Activity

Retinopathy of prematurity (ROP) is characterized by an initial retinal avascularization, followed by pathologic neovascularization. Recently, choroidal thinning has also been detected in children formerly diagnosed with ROP; a similar sustained choroidal thinning is observed in ROP models. But the mechanism underlying the lack of choroidal revascularization remains unclear and was investigated in an oxygen-induced retinopathy (OIR) model. In OIR, evidence of senescence was detected, preceded by oxidative stress in the choroid and the retinal pigment epithelium. This was associated with a global reduction of proangiogenic factors, including insulin-like growth factor 1 receptor (Igf1R). Coincidentally, tumor suppressor p53 was highly expressed in the OIR retinae. Curtailing p53 activity resulted in reversal of senescence, normalization of Igf1r expression, and preservation of choroidal integrity. OIR-induced down-regulation of Igf1r was mediated at least partly by miR-let-7b as i) let-7b expression was augmented throughout and beyond the period of oxygen exposure, ii) let-7b directly targeted Igf1r mRNA, and iii) p53 knock-down blunted let-7b expression, restored Igf1r expression, and elicited choroidal revascularization. Finally, restoration of Igf1r expression rescued choroid thickness. Altogether, this study uncovers a significant mechanism for defective choroidal revascularization in OIR, revealing a new role for p53/let-7b/IGF-1R axis in the retina. Future investigations on this (and connected) pathway could further our understanding of other degenerative choroidopathies, such as geographic atrophy.

Attenuation of Retinal Endothelial Vasodilator Function in a Rat Model of Retinopathy of Prematurity

ABSTRACTPurpose: Retinopathy of prematurity (ROP) is characterized by morphological abnormalities in retinal blood vessels, but how an episode of ROP affects vascular function remains to be fully elucidated. The purpose of the present study was to assess the distribution of pericyte/smooth muscle in retinal blood vessels and retinal vasodilator responses in a rat model of ROP.Methods: ROP was induced in rats by the subcutaneous injection of the vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor KRN633 (10 mg/kg) on postnatal day (P) 7 and P8. The distribution of pericyte/smooth muscle in retinal blood vessels was examined on P14 and P35 by immunohistochemistry. Retinal vasodilator responses were assessed on P35 by measuring the diameter of retinal arterioles in fundus images.Results: In retinas of KRN633-treated (ROP) rats, progressive angiogenesis, tortuous arteries, enlarged veins, and enhanced expression of α-smooth muscle actin in pericytes on capillaries and veins were observed on P14. These abnormalities in retinal vasculature showed a tendency to normalize by P35. Vasodilation of retinal arterioles induced by acetylcholine, an endothelium-dependent vasodilator, was smaller in P35 ROP rats than age-matched controls, whereas retinal vasodilator responses to the nitric oxide (NO) donor NOR3 were unaltered.Conclusions: Phenotypic changes in pericytes occur in the ROP model rats and endothelium-dependent vasodilatory mechanisms in retinal blood vessels are impaired. The impaired vasodilator function may contribute to the progression and pathogenesis of ROP.

The YAP-Elevation Effect of Verteporfin in Retinal Non-Angiogenic Vessels Without Photodynamic Characteristics

Purpose: Verteporfin (VP) is widely used in photodynamic therapy for retinal angiogenesis diseases. It also functions as a Yes-associated protein (YAP) antagonist in tumorigenesis. However, it has been implied that VP has multiple mechanisms in tumor cells and endothelial cells. In this study, we explore the effects of VP in retinal vessels. Methods: Blood samples were collected from patients receiving intravenous vp. Retinas were from mice after VP injection. Western blotting aimed to detect the levels of YAP and Hippo-related proteins in vivo and in vitro. The effect of VP was also tested in a retinopathy of prematurity model. Results: VP dramatically increased YAP and p-YAP levels in patient blood samples and mouse retinas. And YAP were decreased in the U87 cell line but increased in HUVECs. Retinal vascular leakage was significantly alleviated by VP, which similarly to YAP agonist. Conclusion: This study explored the novel effect of VP on YAP activation, and the results suggested tissue-specific effects of VP on YAP bioactivity. Our findings provide new insight into the effects of VP on non-angiogenic vessels without photodynamic characteristics, and VP may be a novel non-invasion therapeutic intervention for ROP. Funding Statement: This research was supported by the National Natural Science Foundation of China (No. 81570840 and No. 81371006), Academician Led Science and Technological Innovation of Chongqing (cstc2017jcyj-yszxX0006) and Research Foundation of Dept. Ophthalmology in Daping Hospital, AMU (No. 9-2543). Declaration of Interests: The authors declare there are no competing interests about this study. Ethics Approval Statement: The study was approved by the Ethics Research Committee of AMU (Permit Number: 2018-31), and all the participants provided informed consent before blood collection. The tenets of the Declaration of Helsinki were adhered to during all procedures of this study. All animal studies were performed in accordance with the ARVO Statement for Use of Animals in Ophthalmic and Vision Research and were approved by the Institutional Animal Care and Use Committee of the Army University.

Endothelial-Specific Deficiency of ATG5 (Autophagy Protein 5) Attenuates Ischemia-Related Angiogenesis.

Objective- Pathological angiogenesis, such as exuberant retinal neovascularization during proliferative retinopathies, involves endothelial responses to ischemia/hypoxia and oxidative stress. Autophagy is a clearance system enabling bulk degradation of intracellular components and is implicated in cellular adaptation to stressful conditions. Here, we addressed the role of the ATG5 (autophagy-related protein 5) in endothelial cells in the context of pathological ischemia-related neovascularization in the murine model of retinopathy of prematurity. Approach and Results- Autophagic vesicles accumulated in neovascular tufts of the retina of retinopathy of prematurity mice. Endothelium-specific Atg5 deletion reduced pathological neovascularization in the retinopathy of prematurity model. In contrast, no alterations in physiological retina vascularization were observed in endothelial-specific ATG5 deficiency, suggesting a specific role of endothelial ATG5 in pathological hypoxia/reoxygenation-related angiogenesis. Consistently, in an aortic ring angiogenesis assay, endothelial ATG5 deficiency resulted in impaired angiogenesis under hypoxia/reoxygenation conditions. As compared to ATG5-sufficient endothelial cells, ATG5-deficient cells displayed impaired mitochondrial respiratory activity, diminished production of mitochondrial reactive oxygen species and decreased phosphorylation of the VEGFR2 (vascular endothelial growth factor receptor 2). Consistently, ATG5-deficient endothelial cells displayed decreased oxidative inactivation of PTPs (phospho-tyrosine phosphatases), likely due to the reduced reactive oxygen species levels resulting from ATG5 deficiency. Conclusions- Our data suggest that endothelial ATG5 supports mitochondrial function and proangiogenic signaling in endothelial cells in the context of pathological hypoxia/reoxygenation-related neovascularization. Endothelial ATG5, therefore, represents a potential target for the treatment of pathological neovascularization-associated diseases, such as retinopathies.

Experimental Evidence Behind Clinical Trial Outcomes in Retinopathy of Prematurity.

Treatment of severe retinopathy of prematurity (ROP) has evolved over the last decade. This article reviews recent clinical trials and experimental evidence that supports clinical outcomes and observations, including the efficacy of anti-vascular endothelial growth factor (VEGF) agents in reducing the vascular activity of severe ROP, and the mechanisms behind recurrent stage 3 ROP and plus disease in some infants treated with anti-VEGF agents. Also discussed will be current imaging modalities that link experimental models of ROP with longitudinal human studies and which provide exciting future opportunities to enhance the understanding of pathophysiology of ROP and improve treatments. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:228-234.].

Protective effects of different bile acids against pathological neovascularization

Emerging evidence suggest that the secondary bile acid ursodeoxycholic acid (UDCA) and its taurine (TUDCA) conjugates, possess neuroprotective and vasculoprotective properties and may exert beneficial effects in a number of neovascular diseases including ischemic retinopathy such as retinopathy of prematurity (ROP). However, the direct activity of UDCA or TUDCA in the treatment of retinal neovascularization has not been previously investigated. Herein, we studied the effects of different bile acids on in vitro angiogenesis in human retinal endothelial cells (HuREC) and retinal vascularization in vivo using the mouse model of oxygen induced retinopathy (OIR), an experimental model of ROP. HuREC were treated with 20 ng/ml of VEGF and/or different doses (10–500 μM) of UDCA or TUDCA for different times. Angiogenic responses were evaluated using tube formation assay. Treatment of HuREC with VEGF significantly induced time dependent tube formation. UDCA dose‐dependently halted VEGF‐induced tube formation, whereas TUDCA had no effect. For the in vivo studies, mice were subjected to OIR and treated with UDCA and TUDCA (administered i.p.) from days P12–P17 (the neovascular stages). Isolectin B4 staining on flat mounted retinal preparations was performed at P17 to evaluate retinal vessel growth and distribution. The results of this analysis revealed that UDCA in the OIR mice halted pathological neovascularization, but did not alter normal vascularization. On the contrary, treatment of the mice with TUDCA failed to block retinal neovascularization, thus confirming the in vitro data. In summary, here we have shown that the bile acids UCDA and TUCDA possess differential ability to modulate VEGF‐mediated angiogenesis effects on HuREC and on retinal pathological neovascularization in vivo. The results of studies support the hypothesis that UDCA could be a potential therapeutic option for ROP as it exerts protection even by systemic administration and does not alter normal progression of vessel formation.Support or Funding InformationThis study is supported by R03HD097660‐01.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Nerve growth factor regulates endothelial cell survival and pathological retinal angiogenesis.

The mechanism underlying vasoproliferative retinopathies like retinopathy of prematurity (ROP) is hypoxia‐triggered neovascularisation. Nerve growth factor (NGF), a neurotrophin supporting survival and differentiation of neuronal cells may also regulate endothelial cell functions. Here we studied the role of NGF in pathological retinal angiogenesis in the course of the ROP mouse model. Topical application of NGF enhanced while intraocular injections of anti‐NGF neutralizing antibody reduced pathological retinal vascularization in mice subjected to the ROP model. The pro‐angiogenic effect of NGF in the retina was mediated by inhibition of retinal endothelial cell apoptosis. In vitro, NGF decreased the intrinsic (mitochondria‐dependent) apoptosis in hypoxia‐treated human retinal microvascular endothelial cells and preserved the mitochondrial membrane potential. The anti‐apoptotic effect of NGF was associated with increased BCL2 and reduced BAX, as well as with enhanced ERK and AKT phosphorylation, and was abolished by inhibition of the AKT pathway. Our findings reveal an anti‐apoptotic role of NGF in the hypoxic retinal endothelium, which is involved in promoting pathological retinal vascularization, thereby pointing to NGF as a potential target for proliferative retinopathies.

Anti-secretogranin III therapy of oxygen-induced retinopathy with optimal safety.

Retinopathy of prematurity (ROP) with pathological retinal neovascularization is the most common cause of blindness in children. ROP is currently treated with laser therapy or cryotherapy, both of which may adversely affect the peripheral vision with limited efficacy. Owing to the susceptibility of the developing retina and vasculatures to pharmacological intervention, there is currently no approved drug therapy for ROP in preterm infants. Secretogranin III (Scg3) was recently discovered as a highly disease-restricted angiogenic factor, and a Scg3-neutralizing monoclonal antibody (mAb) was reported with high efficacy to alleviate oxygen-induced retinopathy (OIR) in mice, a surrogate model of ROP. Herein we independently investigated the efficacy of anti-Scg3 mAb in OIR mice and characterized its safety in neonatal mice. We developed a new Scg3-neutralizing mAb recognizing a distinct epitope and independently established the therapeutic activity of anti-Scg3 therapy to alleviate OIR-induced pathological retinal neovascularization in mice. Importantly, anti-Scg3 mAb showed no detectable adverse effects on electroretinography and developing retinal vasculature. Furthermore, systemic anti-Scg3 mAb induced no renal tubular injury or abnormality in kidney vessel development and body weight gain of neonatal mice. In contrast, anti-vascular endothelial growth factor drug aflibercept showed significant side effects in neonatal mice. These results suggest that anti-Scg3 mAb may have the safety and efficacy profiles required for ROP therapy.

The potential effect of human chorionic gonadotropin on vasoproliferative disorders of the immature retina.

Human chorionic gonadotropin (hCG) is known to be a powerful vascular endothelial growth factor (VEGF)-regulating hormone. It stimulates vascularization of the gravid uterus by upregulating VEGF expression. In the body, hCG activates the same receptor as luteinizing hormone (LH). Like hCG, LH is also strongly proangiogenic. Recently, it has been shown that LH/hCG receptors are present in the retina and that both LH and hCG are found in the eye. In fact, the human eye can synthesize its own hCG. We have previously shown that LH and VEGF are significantly correlated in mammalian eyes, potentially implicating LH-receptor/hCG-receptor activation in intraocular VEGF regulation. Given that elevated VEGF is associated with progression of two vasoproliferative pediatric retinal disorders, retinopathy of prematurity and retinoblastoma, our objective was to determine whether hCG may potentially affect VEGF production and pathologic retinal vascularization in vasoproliferative disorders affecting the immature retina. In this study, we used (a) oxygen-induced retinopathy mouse model (standard model for retinopathy of prematurity) and (b) Y79 retinoblastoma cells (a human cell line derived from immature retinal cells). In the oxygen-induced retinopathy model, number of preretinal nuclei (representing pathologic retinal neovascularization) significantly increases by 57% (P<0.05) in hCG-treated mice. In Y79 cells, VEGF production significantly increases by 37% (P<0.05) in hCG-treated cells. These findings suggest that hCG is potentially able to influence retinal vascularization and VEGF production and thus, the hCG receptor may potentially represent a therapeutic target for vasoproliferative retinal disorders affecting the young eye.

Hematopoietic hypoxia-inducible factor 2α deficiency ameliorates pathological retinal neovascularization via modulation of endothelial cell apoptosis.

A hallmark of proliferative retinopathies, such as retinopathy of prematurity (ROP), is a pathological neovascularization orchestrated by hypoxia and the resulting hypoxia-inducible factor (HIF)-dependent response. We studied the role of Hif2α in hematopoietic cells for pathological retina neovascularization in the murine model of ROP, the oxygen-induced retinopathy (OIR) model. Hematopoietic-specific deficiency of Hif2α ameliorated pathological neovascularization in the OIR model, which was accompanied by enhanced endothelial cell apoptosis. That latter finding was associated with up-regulation of the apoptosis-inducer FasL in Hif2α-deficient microglia. Consistently, pharmacological inhibition of the FasL reversed the reduced pathological neovascularization from hematopoietic-specific Hif2α deficiency. Our study found that the hematopoietic cell Hif2α contributes to pathological retina angiogenesis. Our findings not only provide novel insights regarding the complex interplay between immune cells and endothelial cells in hypoxia-driven retina neovascularization but also may have therapeutic implications for proliferative retinopathies.-Korovina, I., Neuwirth, A., Sprott, D., Weber, S., Sardar Pasha, S. P. B., Gercken, B., Breier, G., El-Armouche, A., Deussen, A., Karl, M. O., Wielockx, B., Chavakis, T., Klotzsche-von Ameln, A. Hematopoietic hypoxia-inducible factor 2α deficiency ameliorates pathological retinal neovascularization via modulation of endothelial cell apoptosis.