Retinal Vascularization Research Articles

Systemic gene therapy rescues retinal dysfunction and hearing loss in a model of Norrie disease.

Deafness affects 5% of the world's population, yet there is a lack of treatments to prevent hearing loss due to genetic causes. Norrie disease is a recessive X-linked disorder, caused by NDP gene mutation. It manifests as blindness at birth and progressive sensorineural hearing loss, leading to debilitating dual sensory deprivation. To develop a gene therapy, we used a Norrie disease mouse model (Ndptm1Wbrg ), which recapitulates abnormal retinal vascularisation and progressive hearing loss. We delivered human NDP cDNA by intravenous injection of adeno-associated viral vector (AAV)9 at neonatal, juvenile and young adult pathological stages and investigated its therapeutic effects on the retina and cochlea. Neonatal treatment prevented the death of the sensory cochlear hair cells and rescued cochlear disease biomarkers as demonstrated by RNAseq and physiological measurements of auditory function. Retinal vascularisation and electroretinograms were restored to normal by neonatal treatment. Delivery of NDP gene therapy after the onset of the degenerative inner ear disease also ameliorated the cochlear pathology, supporting the feasibility of a clinical treatment for progressive hearing loss in people with Norrie disease.

Novel Function of Nogo-A as Negative Regulator of Endothelial Progenitor Cell Angiogenic Activity: Impact in Oxygen-Induced Retinopathy.

Endothelial Progenitor Cells (EPCs) can actively participate in revascularization in oxygen-induced retinopathy (OIR). Yet the mechanisms responsible for their dysfunction is unclear. Nogo-A, whose function is traditionally related to the inhibition of neurite function in the central nervous system, has recently been documented to display anti-angiogenic pro-repellent properties. Based on the significant impact of EPCs in retinal vascularization, we surmised that Nogo-A affects EPC function, and proceeded to investigate the role of Nogo-A on EPC function in OIR. The expression of Nogo-A and its specific receptor NgR1 was significantly increased in isolated EPCs exposed to hyperoxia, as well as in EPCs isolated from rats subjected to OIR compared with respective controls (EPCs exposed to normoxia). EPCs exposed to hyperoxia displayed reduced migratory and tubulogenic activity, associated with the suppressed expression of prominent EPC-recruitment factors SDF-1/CXCR4. The inhibition of Nogo-A (using a Nogo-66 neutralizing antagonist peptide) or siRNA-NGR1 in hyperoxia-exposed EPCs restored SDF-1/CXCR4 expression and, in turn, rescued the curtailed neovascular functions of EPCs in hyperoxia. The in vivo intraperitoneal injection of engineered EPCs (Nogo-A-inhibited or NgR1-suppressed) in OIR rats at P5 (prior to exposure to hyperoxia) prevented retinal and choroidal vaso-obliteration upon localization adjacent to vasculature; coherently, the inhibition of Nogo-A/NgR1 in EPCs enhanced the expression of key angiogenic factors VEGF, SDF-1, PDGF, and EPO in retina; CXCR4 knock-down abrogated suppressed NgR1 pro-angiogenic effects. The findings revealed that hyperoxia-induced EPC malfunction is mediated to a significant extent by Nogo-A/NgR1 signaling via CXCR4 suppression; the inhibition of Nogo-A in EPCs restores specific angiogenic growth factors in retina and the ensuing vascularization of the retina in an OIR model.

Treatment of Retinopathy of Prematurity by Intravitreal Injection of Bevacizumab

Introduction: Retinopathy of prematurity is a vasoproliferative disease of the developing retina that is a significant cause of paediatric morbidity and blindness worldwide. Although management by early treatment ROP (ETROP) criteria has led the way to improving the outcomes of treatment-requiring posterior (zone 1) ROP, the failure rate continues to be significant for aggressive disease. Managing a premature infant with ROP is a significant challenge to ophthalmologists and associated physicians. However, increasingly younger and lower birth-weight infants can survive with advances in neonatal care. Objectives: To assess the effectiveness of intravitreal injection of Bevacizumab on regression of retinal neovascularization in stage III, Zone 1, 2 retinopathy of prematurity and aggressive posterior retinopathy of prematurity. Methods: Intravitreal Injection of Bevacizumab (0.625mg/0.025mL) was performed on 34 eyes of 17 newborns with stage III, Zone 1, 2 retinopathy of prematurity and aggressive posterior retinopathy of prematurity. The changes in retinal neovascularization were assessed by frequent fundoscopy. Results: Retinopathy of prematurity regressed in all the eyes treated. The retinal vascularization proceeded beyond the demarcation line. Four eyes of 2 patients needed repeat injections. One eye needed an additional laser. There was no injection-related complication observed. Conclusion: Intravitreal injection of Bevacizumab can be considered an effective modality in treating Retinopathy of Prematurity. It is recommended to perform more studies to assess its long-term effect on the body's vascular system. JAFMC Bangladesh. Vol 18, No 2 (December) 2022: 24-27

Identifying Clinical Predictors of Proliferative Sickle Cell Retinopathy

Purpose To identify systemic and/or ophthalmologic predictors of proliferative sickle retinopathy. Methods Cross-sectional study comparing clinical, laboratory, and structural choriorretinal aspects between sickle cell disease patients with and without proliferative retinopathy. Patients underwent complete systemic and ophthalmologic evaluation. Enhanced depth spectral domain optical coherence tomography with choroidal binarization and optic coherence tomography angiography were performed and choriorretinal vascular components were compared. Results Forty-five eyes from 45 sickle cell patients were included. Ninety-one percent of patients were diagnosed with sickle cell retinopathy, 29% with proliferative retinopathy. Mean corpuscular volume, lactate dehydrogenase, and percentage of fetal hemoglobin were reduced in the subgroup of patients with proliferative retinopathy when compared with patients without proliferative retinopathy (p ≤ 0.001; p = 0.04; p ≤ 0.001, respectively). The best predictor of proliferative retinopathy was mean corpuscular volume (AUC = 0.842; p = 0.001), followed by the percentage of fetal hemoglobin (AUC = 0.763, p = 0.009) and lactate dehydrogenase (AUC curve = 0.706; p = 0.039). No differences were found between groups in the quantitative analysis of retinal vascularization using OCTA and choroidal vascularization using OCT (p ≥ 0.05). Conclusion Fetal hemoglobin and mean corpuscular volume may be good predictors of proliferative sickle retinopathy. The association between proliferative retinopathy and reduced levels of lactate dehydrogenase and mean corpuscular volume points to hypoxia and not hemolysis as a possible driving force in its pathophysiology.

Risk factors of immature retina on the first screening for retinopathy of prematurity

Background Immature retina is characterized by peripheral retinal avascularity. Retinal development is influenced by risk factors that affect retinal maturity.
 Objective To identify risk factors for immature retina on the first retinopathy of prematurity (ROP) screening at the Neonatology Care Unit, Al-Islam Hospital, Bandung, in 2013-2021.
 Methods This case-control, retrospective, observational study was performed by evaluating medical records of preterm infants screened for ROP. The subjects were divided into two groups, immature retina and mature retina. We recorded potential risk factors including gestational age (GA), birth weight (BW), birth weight for gestational age, respiratory distress syndrome (RDS), oxygen therapy >7 days, asphyxia, sepsis, multiple transfusion, apnea of prematurity (AOP), patent ductus arteriosus (PDA), and bronchopulmonary dysplasia (BPD) and analyzed them for potential associations with retinal development.
 Results On the first ROP screening of 203 premature infants, 5 (2.5%) had ROP, 90 (44.6%) had immature retinas, and 107 (53.0%) had mature retinas. Bivariate logistic regression analysis showed significant relationships between immature retina (P<0.05), GA (OR=0.575; P=0.000), BW (OR=0.997; P=<0.001), gestational age maturity (OR=2.639; P=0.006), RDS (OR=1.809; P=0.042), oxygen therapy of >7 days (OR=4.494; P=0.002), sepsis (OR=2.028; P=0.034), multiple transfusions (OR=4.656; P=0.000), AOP (OR=2.553; P=0.002), PDA (OR=2.119; P=0.030). Multivariate regression analysis revealed a significant simultaneous relationship between all the risk factors and immature retina, with a Nägelkerke R2 value of 0.421.
 Conclusion GA, BW, gestational age maturity, oxygen therapy of >7 days, sepsis, multiple transfusions, AOP, and PDA are significant risk factors of immature retina, be it independently or simultaneously.

Retinal capillary and choriocapillaris assessment using a beam modifier optical coherence tomography angiography module to increase lateral optical resolution.

To assess a new optical coherence tomography angiography (OCTA) technology and its contribution to retinal vascularization and choriocapillaris (CC) exploration. A new module, named "Beam expander" (BE), which increases the lateral resolution of OCTA, was used in combination with a prototype software in the PLEX® Elite 9000 Swept-Source OCT instrument (ZEISS, Dublin, CA). This prospective study involved 22 healthy subjects imaged with and without BE. Qualitative analysis of superficial capillary plexus (SCP), deep capillary complex (DCC) retinal and CC angiograms were performed. Perfusion density (PD), vessel density (VD), and foveal avascular zone (FAZ) measurements were also compared. Qualitative analysis of single SCP and DCC retinal angiograms acquired with BE showed significantly better vessel sharpness (respectively, p = 0.0002, and p<0.0001), and greater peripheral image quality (p = 0.028 and p = 0.007) compared to standard OCTA images. Mean VD of whole retina single scans was significantly higher for BE angiograms compared to classic angiograms (28.16 ±1.29 mm-1 and 23.36 ±0.92 mm-1, respectively, p<0.0001). Repeatability of VD, PD and FAZ raw size were found to be similar between the two methods (intraclass correlation coefficient: 0.671, 0.604 and 0.994 with BE versus 0.764, 0.638 and 0.990 without BE). CC image quality was found to be significantly superior with BE, and flow deficits were more visible in all BE scans compared to standard scans. An increase in lateral resolution of the OCT beam resulted in higher quality of retinal and choriocapillaris OCTA images in healthy subjects. These results provide significant insights into the future OCTA imaging enhancements.

Quantitative evaluation of retinal and choroidal vascularity in systemic lupus erythematosus by SS-OCT/OCTA.

To evaluate changes in retinal and choroidal vascularity using swept-source optical coherence tomography (SS-OCT) and optical coherence tomography angiography (OCTA) in patients with systemic lupus erythematosus (SLE). In this prospective, cross-sectional study, 48 SLE patients and 40 healthy control (group HC) participants were included. The SLE patients were divided into two subgroups: patients with SLE with no ocular disease (group I) and patients with SLE with signs of retinopathy (group II). The superficial vessel density (SVD), deep vessel density (DVD), peripapillary retinal vessel densities (pRVD), choroidal thickness (ChT), and choroidal vascularity including total choroidal area (TCA), luminal area (LA), stromal area (SA), and choroidal vascularity index (CVI) were measured using SS-OCT/OCTA. Physical and ophthalmic examinations as well as the assessments of immunological markers were performed. The results of SS-OCT/OCTA were compared between group I, group II, and group HC, while the correlations among the parameters were analyzed. The SVD, DVD, and pRVD were found to be significantly lower in SLE patients than group HC, especially in SLE patients with signs of retinopathy. ChT were found to be significantly higher in group II. CVI was positively correlated with SVD and DVD in the fovea, as well as the foveal and parafoveal thickness. A significant decrease in SVD and DVD in the fovea among subjects positive for anti-dsDNA antibodies was noted. The application of OCTA in the evaluation of microvasculature may be useful in subclinical changes. Retinal microvascular density decreased in patients with SLE with greater severity of SLE. Disturbed retinal circulation was related to SLE disease activity, disease duration, CVI, and being positive for anti-dsDNA antibodies. The study results also suggest that SLE with signs of retinopathy may affect the choroid with increases in LA, SA, TCA, and ChT.

Incomplete peripheral retinal vascularisation in retinopathy of prematurity: is it the consequence of changing oxygen saturation?

We wish to determine the prevalence and risk factors of incomplete peripheral avascular retina (IPAR) in children screened for retinopathy of prematurity (ROP) and its association with oxygen saturation (SpO2) targets. A retrospective review of retinal images of premature infants born and screened for ROP in Auckland Region, New Zealand, between January 2013 and December 2017 was conducted. Images were reviewed to determine if avascular retina was present at their final ROP screening. The prevalence of peripheral avascular retina was compared among infants born prior to (Group 1) and after (Group 2) 2015 when the SpO2 target was increased. Infants with any concurrent ocular pathology or who had received ROP treatment were excluded. In total, 62 (12.8%) of the total of 486 infants (247 in Group 1; 239 in Group 2) were found to have IPAR at their last ROP screening. Group 1 had more statistically significant infants with IPAR compared to Group 2 (39/247 infants and 23/239 infants respectively; p = 0.043). Incomplete peripheral retinal vascularisation occurred at a prevalence of 12.8% in infants at risk of ROP. Higher SpO2 targets did not increase the prevalence of incomplete peripheral retinal vascularisation. Low gestational age and low birth weight are likely risk factors for the development of avascular retina. Further research into the risk factors associated with incomplete peripheral retinal vascularisation and the associated long-term outcomes is needed.

Quantitative Parameters Relevant for Diabetic Macular Edema Evaluation by Optical Coherence Tomography Angiography.

Diabetic macular edema (DME) is one of the main ocular complications of diabetes mellitus (DM) that can lead to important vision loss in diabetic patients. In clinical practice, there are cases of DME with unsatisfying treatment responses, despite adequate therapeutic management. Diabetic macular ischemia (DMI) is one of the causes suggested to be associated with the persistence of fluid accumulation. Optical coherence tomography angiography (OCTA) is a non-invasive imaging modality, able to give in-depth information about retinal vascularization in a 3-dimensional manner. The OCTA devices currently available can provide various OCTA metrics that quantitatively assess the retinal microvasculature. In this paper, we reviewed the results of multiple studies that investigated the changes in OCTA metrics in the setting of DME and their possible contribution to the diagnosis, therapeutic management, follow-up and prognosis of patients with DME. We analyzed and compared relevant studies that investigated OCTA parameters related to changes in macular perfusion in the setting of DME and we evaluated the correlations between DME and several quantitative parameters, such as vessel density (VD), perfusion density (PD), foveal avascular zone (FAZ)-related parameters, as well as complexity indices of retinal vasculature. The results of our research showed that OCTA metrics, evaluated especially at the level of the deep vascular plexus (DVP), are useful instruments that can contribute to the assessment of patients with DME.

Impact of postnatal steroids on peripheral avascular retina and severity of retinopathy of prematurity.

We investigated the role of postnatal steroids on the severity of retinopathy of prematurity (ROP) and its impact on peripheral avascular retina (PAR). A retrospective cohort study of infants born at ≤32 weeks gestation and/or birth weight ≤1500 g. Demographics, the dose and duration of steroid treatment, and age when full retinal vascularization occurred were collected. The primary outcomes were the severity of ROP and time to full vascularization of the retina. A total of 1695 patients were enrolled, 67% of whom received steroid therapy. Their birth weight was 1142 ± 396 g and gestational age was 28.6 ± 2.7 weeks. The total hydrocortisone-equivalent dose prescribed was 28.5 ± 74.3 mg/kg. The total days of steroid treatment were 8.9 ± 35.1 days. After correction for major demographic differences, infants who received a higher cumulative dose of steroids for a longer duration had a significantly increased incidence of severe ROP and PAR (P < 0.001). For each day of steroid treatment, there was a 3.2% increase in the hazard of the severe form of ROP (95% CI: 1.022-1.043) along with 5.7% delay in achieving full retinal vascularization (95% CI: 1.04-1.08) (P < 0.001). Cumulative dose and duration of postnatal steroid use were independently associated with the severity of ROP and PAR. Thus, postnatal steroids should be used very prudently. We report ROP outcomes in a large cohort of infants from two major healthcare systems where we have studied the impact of postnatal steroids on the severity of ROP, growth, and development of retinal vessels. After correcting our data for three major outcome measures, we show that high-dose postnatal steroids used for a prolonged duration of time are independently associated with severe ROP and delay in retinal vascularization. Postnatal steroids impact the visual outcomes of VLBW infants significantly, so their clinical use needs to be moderated.

Comparison of Retinal and Choroidal Microvasculature Changes in Monocular Amblyopic and Non-amblyopic Eyes following Short-term Patch Occlusion Treatment

Purpose Our objective was to investigate whether there were differences in the short-term changes of retinal and choroidal microvasculature between amblyopic and non-amblyopic eyes after patch occlusion treatment in patients with monocular amblyopia. Additionally, we aimed to determine if these changes were associated with improvements in clinical parameters. Methods We conducted a retrospective, longitudinal paired-eye case-control study by analyzing the medical records of patients under the age of 12 who had monocular amblyopia and underwent patch occlusion treatment for a duration of 2 to 12 months. Using optical coherence tomography angiography images, we compared the foveal avascular zone width, retinal blood vessel density (VD), choroidal thickness (CT), and choroidal vascularity index (CVI) in amblyopic and non-amblyopic eyes before and after patch occlusion treatment. We analyzed the correlations between the aforementioned parameters and changes in best-corrected visual acuity (BCVA) and stereopsis. Results Overall, 114 eyes from 57 patients were enrolled. At baseline, parafoveal superficial plexus VD, foveal and parafoveal deep capillary plexus VD (DCPD) were lower by 0.994 ± 3.312% (p = .026), 2.403 ± 8.273% (p = .033), and 2.469 ± 4.095% (p < .001), respectively; CT was thicker by 30.6 ± 90.7 μm (p = .014); and CVI was higher by 1.920 ± 3.432% (p < 001) in the amblyopic eyes than in the non-amblyopic eyes. Following short-term patch occlusion treatment, foveal and parafoveal DCPD increased by 1.264 ± 3.829% (p = .017) and 1.028 ± 3.662% (p = .036), respectively, CT thinned by 15.5 ± 51.5 μm (p = .019), and CVI decreased by 1.296 ± 3.997% (p = .018) in the amblyopic eyes. Following patch occlusion treatment, as the foveal DCPD decreased and CVI increased, the BCVA improved (p = .017 and .035, respectively). Conclusion Following patch occlusion treatment, increased foveal DCPD and decreased CVI were associated with improved BCVA.

Electron, Photon, and Neutron Dose Conversion Coefficients of Lens and Non-Lens Tissues Using a Multi-Tissue Eye Model to Assess Risk of Cataracts and Retinitis.

Previous publications describe the estimation of the dose from ionizing radiation to the whole lens or parts of it but have not considered other eye tissues that are implicated in cataract development; this is especially critical for low-dose, low-ionizing-density exposures. A recent review of the biological mechanisms of radiation-induced cataracts showed that lenticular oxidative stress can be increased by inflammation and vascular damage to non-lens tissues in the eye. Also, the radiation oxygen effect indicates different radiosensitivities for the vascular retina and the severely hypoxic lens. Therefore, this study uses the Monte Carlo N-Particle simulations to quantify dose conversion coefficients for several eye tissues for incident antero-posterior exposure to electrons, photons, and neutrons (and the tertiary electron component of neutron exposure). A stylized, multi-tissue eye model was developed by modifying a model by Behrens etal. (2009) to include the retina, uvea, sclera, and lens epithelial cell populations. Electron exposures were simulated as a single eye, whereas photon and neutron exposures were simulated employing two eyes embedded in the ADAM-EVA phantom. For electrons and photons, dose conversion coefficients are highest for either anterior tissues for low-energy incident particles or posterior tissues for high-energy incident particles. Neutron dose conversion coefficients generally increase with increasing incident energy for all tissues. The ratio of the absorbed dose delivered to each tissue to the absorbed dose delivered to the whole lens demonstrated the considerable deviation of non-lens tissue doses from lens doses, depending on particle type and its energy. These simulations demonstrate that there are large variations in the dose to various ocular tissues depending on the incident radiation dose coefficients; this large variation will potentially impact cataract development.

Quantitative Evaluation of Progression of Retinal Vascularization After 60 Weeks Postmenstrual Age in Infants Treated With Bevacizumab.

To investigate the progression of retinal vascularization after 60 weeks postmenstrual age (PMA) in eyes treated with intravitreal bevacizumab (IVB). Twenty-seven eyes that were treated with IVB and underwent two consecutive fluorescein angiographies (FA) after 60 weeks PMA. Horizontal disc diameter (DD), disc-to-fovea (DF) distance, and length of temporal retinal vascularization (LTRV) were measured in pixels on the two consecutive angiograms. Mean age at first and final FA sessions were 77.7 ± 15.7 and 168.0 ± 49.0 weeks PMA, respectively. The DF/DD ratio was 3.30 ± 0.46 and 3.16 ± 0.46 in the first and final FAs (P = 0.001), respectively. The LTRV/DD ratio was 13.38 ± 2.12 and 13.15 ± 2.13 in the first and final FAs (P = 0.027), respectively. The LTRV/DF ratio was 4.06 ± 0.39 and 4.17 ± 0.42, respectively (P = 0.032). Temporal retinal vascularization did not progress despite an average follow-up of 90 weeks in pixel units and DD. [Ophthalmic Surg Lasers Imaging Retina 2023;54:417-424.].

An 82-year-old woman with retinal vascular sheathing and vitreous hemorrhage.

This report describes a case of hereditary transthyretin amyloidosis in an 82-year-old woman who presented with bilateral retinal arteriolar vascular sheathing and vitreous hemorrhage in one eye. The patient underwent a full history, physical examination, genetic workup, and cardiac imaging to establish the diagnosis. Fundus photographs, optical coherence tomography, fluorescein angiography, and indocyanine green angiography were performed throughout the patient's treatment course. Fundus examination demonstrated segmental sheathing of the retinal arterioles, telangiectasias, and intraretinal hemorrhages in both eyes without neovascularization. Fluorescein angiography revealed delayed filling of the nasal retinal arterioles in the right eye with severe temporal nonperfusion and areas hyperfluorescent segmental sheathing in both eyes. Ocular coherence tomography demonstrated retinal vessels with hyperreflective thickened walls. Cardiac amyloid nuclear scan was consistent with transthyretin-mediated amyloidosis amyloid heart disease, and genetic testing confirmed a heterozygous pathogenic transthyretin mutation: c.290 C>A (p.Ser97Tyr) also known as Ser77Tyr. Amyloidosis should be considered in the differential of vasculitis and vitreous hemorrhage with or without significant vitreous opacities. Ophthalmologists aware of this diagnosis should complete a full review of systems with specific focus on cardiac history and symptoms of peripheral neuropathy when amyloidosis is in the differential.

Reduced Vessel Density and Enlarged Foveal Avascular Zone in the Macula as a Result of Systemic Hypoxia Caused by SARS-CoV-2 Infection.

Infection with SARS-CoV-2 can lead to various long-term consequences, including those of an ophthalmic nature. This paper reviews the results of optical coherence tomography angiography (OCTA) performed among COVID-19 patients. The review included papers evaluating short- and long-term outcomes following the SARS-CoV-2 infection. Some differentiated the obtained retinal and choroidal vascularization parameters according to gender. Following COVID-19, patients reveal changes in retinal and choroidal vascular parameters based on OCTA, such as reduced vascular density and an increased foveal avascular zone, which can persist for several months. Routine ophthalmic follow-up with OCTA should be considered in patients after SARS-CoV-2 infection to assess the effects of inflammation and systemic hypoxia in COVID-19. Further research is needed to understand whether infection with particular viral variants/subvariants may vary in the risk of effects on retinal and choroidal vascularization and whether and to what extent these risks may also differ in relation to reinfected and vaccinated individuals.

Vitreoretinal biomarkers of retinopathy of prematurity using handheld optical coherence tomography: a review.

Retinopathy of prematurity (ROP) is caused by abnormal retinal vascularization in premature infants that has the potential for severe long-term vision impairment. Recent advancements in handheld optical coherence tomography (OCT) have enabled noninvasive, high-resolution, cross-sectional imaging of the infant eye at the bedside. The use of handheld OCT devices in the diagnosis of ROP in premature infants has furthered our understanding of disease state and progression. This review discusses the known and novel biomarkers of ROP severity in premature infants identified through handheld OCT and potential for future directions.

Fibrillin-1 regulates endothelial sprouting during angiogenesis

Fibrillin-1 is an extracellular matrix protein that assembles into microfibrils which provide critical functions in large blood vessels and other tissues. Mutations in the fibrillin-1 gene are associated with cardiovascular, ocular, and skeletal abnormalities in Marfan syndrome. Here, we reveal that fibrillin-1 is critical for angiogenesis which is compromised by a typical Marfan mutation. In the mouse retina vascularization model, fibrillin-1 is present in the extracellular matrix at the angiogenic front where it colocalizes with microfibril-associated glycoprotein-1, MAGP1. In Fbn1C1041G/+ mice, a model of Marfan syndrome, MAGP1 deposition is reduced, endothelial sprouting is decreased, and tip cell identity is impaired. Cell culture experiments confirmed that fibrillin-1 deficiency alters vascular endothelial growth factor-A/Notch and Smad signaling which regulate the acquisition of endothelial tip cell/stalk cell phenotypes, and we showed that modulation of MAGP1 expression impacts these pathways. Supplying the growing vasculature of Fbn1C1041G/+ mice with a recombinant C-terminal fragment of fibrillin-1 corrects all defects. Mass spectrometry analyses showed that the fibrillin-1 fragment alters the expression of various proteins including ADAMTS1, a tip cell metalloprotease and matrix-modifying enzyme. Our data establish that fibrillin-1 is a dynamic signaling platform in the regulation of cell specification and matrix remodeling at the angiogenic front and that mutant fibrillin-1-induced defects can be rescued pharmacologically using a C-terminal fragment of the protein. These findings, identify fibrillin-1, MAGP1, and ADAMTS1 in the regulation of endothelial sprouting, and contribute to our understanding of how angiogenesis is regulated. This knowledge may have critical implications for people with Marfan syndrome.

Incomplete retinal vascularization with retinopathy of prematurity-like ridges in healthy full-term newborns.

To describe the characteristics and clinical course of retinopathy of prematurity (ROP)-like ridges in healthy full-term newborns. A retrospective medical record review was performed on newborns who underwent fundus photography within 72h of birth between January 1st and December 31st, 2019 at Women & Children's Health Care Hospital of Huantai, China. The RetCam 3 wide-field digital imaging system was used for fundus photography. ROP-like ridges were discovered and described. Total of 5507 full-term infants underwent fundus photography. ROP-like ridges were discovered in 90 eyes from 57 infants (1.0%). Stage 1 ROP-like was seen in 63 of the eyes (70%), Stage 2 ROP-like in 26 of the eyes (28.9%), and Stage 3 ROP-like in 1 eye (1.1%). These ROP-like ridges were found in Zone II (41.1%) and Zone III (58.9%), but not in Zone I. Eight (8.9%) of the eyes had pre-plus-like diseases. No eyes had plus disease. All ROP-like ridges and pre-plus-like diseases were spontaneously regressed with a mean duration of 39.0 ± 8.2days. Male sex (P = 0.003) was positively associated with ROP-like changes. Healthy full-term newborns may have incomplete retinal vascularization and ROP-like ridges at birth. These ROP-like ridges showed signs of spontaneous regression.

Retinal and Choroidal Alterations in Diabetic Retinopathy Treatment using Subthreshold Panretinal Photocoagulation with Endpoint Management Algorithm: A Secondary Analysis of a Randomized Clinical Trial.

The aim of this study was to compare retinal and choroidal alterations in eyes with severe nonproliferative diabetic retinopathy (NPDR) after panretinal photocoagulation (PRP), using conventional pattern scan laser (PASCAL) and PASCAL with endpoint management (EPM). This was a post hoc analysis of a paired randomized clinical trial. Bilateral treatment-naïve eyes of an individual with symmetric severe NPDR were randomly allocated into the threshold PRP group and subthreshold EPM PRP group. Patients had follow-up visits at 1, 3, 6, 9, and 12months post-treatment. The retinal thickness (RT), choroidal thickness (CT), choroidal area, and choroidal vascularity index (CVI) were compared between the two groups and among different time points within the same group. Seventy eyes of 35 patients with diabetes mellitus (DM) were finally included for analysis at the 6- and 12-month visits, respectively. At 3 and 6months post-treatment, the RT in the subthreshold EPM PRP group was significantly thinner than that in the threshold PRP group. CT, stromal area, and luminal area were reduced earlier in the threshold PRP group than in the subthreshold EPM PRP group. CVI was not significantly different within the same group or between groups at most time points. At 12months post-treatment, retinal thickening and choroidal disturbance may be slightly less severe and more delayed in eyes receiving PRP using PASCAL with EPM than in those receiving PRP using conventional PASCAL. The EPM algorithm may be a good alternative in PRP when treating severe NPDR. ClinicalTrials.gov identifier, NCT01759121.

Decreased Macular Choriocapillaris Perfusion in Eyes With Macular Reticular Pseudodrusen Imaged With Swept-Source OCT Angiography.

To determine if macular reticular pseudodrusen (RPD) were associated with markers of impaired macular choroidal perfusion, we investigated measurements of macular choriocapillaris (CC) flow deficits (FDs), CC thickness, and mean choroidal thickness (MCT) in eyes with macular RPD compared with normal eyes and eyes with soft drusen. Eyes with intermediate age-related macular degeneration (iAMD) and normal eyes underwent 6 × 6 mm swept-source optical coherence tomography angiography (SS-OCTA) imaging to diagnose macular RPD, occupying over 25% of the fovea-centered 5 mm diameter circle, and measure outer retinal layer (ORL) thickness, CC FDs, CC thickness, MCT, and choroidal vascularity index (CVI) using previously published strategies within the same fovea-centered 5 mm circle. Ninety eyes were included; 30 normal eyes, 30 eyes with soft drusen, and 30 eyes with macular RPD. The RPD eyes showed higher macular CC FDs than normal eyes (P < 0.001) and soft drusen eyes (P = 0.019). Macular CC thickness was decreased in RPD eyes compared with normal eyes (P < 0.001) and soft drusen eyes (P = 0.016). Macular MCT in RPD eyes was thinner than normal eyes (P = 0.005) and soft drusen eyes (P < 0.001). No statistically and clinically significant differences were found in the ORL thickness and CVI measurements between RPD eyes and the other two groups (all P > 0.05). Eyes with macular RPD had decreased macular CC perfusion, decreased CC thickness, and decreased MCT measurements compared with normal and soft drusen eyes, suggesting that RPD may result from impaired choroidal perfusion.