Superficial Retinal Vascular Plexus Research Articles

Evaluation of Circulating Platelet Extracellular Vesicles and Hypertension Mediated Organ Damage.

Elevated circulating platelet-derived extracellular vesicles (pEVs) have been associated with arterial hypertension. The role of hypertension-mediated organ damage (HMOD) to induce EV release is still unknown. We studied the micro- and macro-vascular changes (retinal vascular density and pulse wave velocity), endothelial function (flow-mediated vasodilation of brachial artery and finger plethysmography), and assessed the psychosocial status (anxiety and depression) in hypertensive patients to determine their relationship with EV release. Pulse wave velocity showed a significant positive correlation with pEVs (r = 0.33; p = 0.01). Systolic blood pressure (SBP) negatively correlated with retinal vascularity. The superficial retinal vascular plexus density in the whole image showed a significant negative correlation with 24 h SBP (r = −0.38, p < 0.01), day-SBP (r = −0.35, p = 0.01), and night-SBP (r = −0.27, p = 0.04). pEVs did not show significant associations with microvascular damage (retinal vascular density), endothelial function (flow-mediated vasodilation of brachial artery and finger plethysmography), or psychosocial status (anxiety and depression). Our results indicate that the pEV levels were associated with macrovascular damage measured by PWV, whereas no significant association between pEVs and microvascular damage, endothelial function, or emotional status could be detected. The potential utility of pEV in clinical practice in the context of HMOD may be limited to macrovascular changes.

Specialized endothelial tip cells guide neuroretina vascularization and blood-retina-barrier formation.

Endothelial tip cells guiding tissue vascularization are primary targets for angiogenic therapies. Whether tip cells require differential signals to develop their complex branching patterns remained unknown. Here, we show that diving tip cells invading the mouse neuroretina (D-tip cells) are distinct from tip cells guiding the superficial retinal vascular plexus (S-tip cells). D-tip cells have a unique transcriptional signature, including high TGF-β signaling, and they begin to acquire blood-retina barrier properties. Endothelial deletion of TGF-β receptor I (Alk5) inhibits D-tip cell identity acquisition and deep vascular plexus formation. Loss of endothelial ALK5, but not of the canonical SMAD effectors, leads to aberrant contractile pericyte differentiation and hemorrhagic vascular malformations. Oxygen-induced retinopathy vasculature exhibits S-like tip cells, and Alk5 deletion impedes retina revascularization. Our data reveal stage-specific tip cell heterogeneity as a requirement for retinal vascular development and suggest that non-canonical-TGF-β signaling could improve retinal revascularization and neural function in ischemic retinopathy.

Retinal OCT Findings in Patients after COVID Infection

Purpose: The aim of this study was to assess and compare the optic nerve, retina, and retinal vessel parameters in recovered COVID-19 patients and healthy patients by using optical coherence tomography angiography (OCT-a). Methods: In all, 156 eyes of post-COVID-19 patients and 98 eyes of subjects from a control group were enrolled in our study. BCVA, intra ocular pressure (IOP) measurement, fundus examination, and OCT images, including macular cube, OCT-RNFL, and angio-OCT 6 × 6 mm examinations, were performed for both groups. The measurements were acquired using Swept Source OCT DRI OCT Triton. In the post-COVID-19 group, 762 OCT protocols were obtained. For statistical analysis, parameters from only one eye from each subject were taken. Results: In the measured parameters, no significant differences were observed, i.e., central macular thickness (p = 0.249); RNFL (p = 0.104); FAZ (p = 0.63); and vessel density of superficial retinal vascular plexus in central (p = 0.799), superior (p = 0.767), inferior (p = 0.526), nasal (p = 0.402), and temporal (p = 0.582) quadrants. Furthermore, a slit-lamp examination did not reveal any COVID-19-related abnormalities. Conclusion: OCT examination did not detect any significant changes in morphology or morphometry of the optic nerve, retina, or the retina vessels due to COVID-19.

Normative Data of Superficial Retinal Vascular Plexus and the Relationship to Retinal Layers.

Objectives:The aim of this study was to evaluate the relationship between optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) parameters in a healthy population and to detect any changes that occur with age.Methods:A total of 100 healthy participants were included in this prospective, observational, and comparative study. The participants were categorized in 4 groups according to age: Group 1: 21-30 years, Group 2: 31-40 years, Group 3: 41-50 years, Group 4: 51-60 years of age. Mean macular thickness, retinal nerve fiber layer (RNFL), ganglion cell inner plexiform layer (GC-IPL), and the choroidal thickness (ChT), vessel density (VD), perfusion density (PD), foveal avascular zone (FAZ), and parapapillary perfusion density parameters were recorded and analyzed.Results:In comparisons between groups, no significant difference in OCTA parameters was observed. There were inverse correlations between the outer VD, PD, and intraocular pressure (IOP) (r= -0.307, p=0.006 and r= -0.284, p=0.011, respectively). The correlation between parapapillary perfusion density and IOP was close to being significant (r= -0.213, p=0.059). There were significant relationships between OCTA parameters and macular, RNFL, and GC-IPL thickness. No significant relationship between ChT and OCTA parameters was seen.Conclusion:The size and characteristics of superficial VD, PD, parapapillary perfusion density, and FAZ were determined in a population with standardized demographic and ocular clinical features, and the relationship between these parameters and retinal layers was established.

Клинико-функциональная оценка эффективности лечения макулярного отека на фоне тромбоза центральной вены сетчатки и ее ветвей

«Российская офтальмология онлайн» - электронное информационное издание, создается с 1 марта 2010 года под эгидой Российского общества офтальмологов. Основная задача проекта - научно-информационная поддержка специалистов в области офтальмологии.

Assessment of macular vascular plexus density using optical coherence tomography angiography in cases of strabismic amblyopia.

Purpose:To evaluate the superficial retinal vascular plexus density using optical coherence tomography angiography (OCTA) in cases of strabismic amblyopia.Methods:Ten eyes of 10 patients with purely strabismic amblyopia underwent detailed ocular evaluation followed by the assessment of the superficial retinal plexus vascular density using OCTA (Topcon DRI OCT Triton, Swept Source OCT, Topcon, Japan). Ten contralateral normal eyes of the same patients were considered as control. All these 20 eyes underwent a 4.5 × 4.5 mm cube scan OCTA centered at the fovea. Using the Topcon propriety software all 20 eyes were assessed for the capillary plexus density of the superficial retinal vascular plexus along the superior, inferior, nasal, and temporal quadrants centered at the fovea. The numerical values were statistically assessed using a paired t-test with respect to each quadrant between the normal and the pathological eyes.Results:The average age of patients was 16 years and eight patients were males. The mean superficial retinal vascular plexus density along the superior, inferior, nasal, and temporal quadrants in normal and pathological eyes were 49.25 ± 30.34 and 48.93 ± 2.85, 47.22 ± 4.11 and 47.37 ± 4.8, 45.54 ± 1.55 and 43.81 ± 4.21, and 46.26 ± 4.63 and 46.38 ± 5.40, respectively. Similarly, the capillary densities along the central were 17.84 ± 3.49 and 17.24 ± 2.44 in normal and pathological eyes. The differences among all these four quadrants and central area were not statistically significant (P-values > 0.05 for all four quadrants and central area) as compared with the normal eyes.Conclusion:The superficial retinal vascular plexus density of a 4.5 × 4.5 mm cube centered at the fovea of eyes of cases of strabismic amblyopia is similar to that of normal eyes.

Quantitative Proteomics Reveals β2 Integrin-mediated Cytoskeletal Rearrangement in Vascular Endothelial Growth Factor (VEGF)-induced Retinal Vascular Hyperpermeability

Retinal vascular hyperpermeability causes macular edema, leading to visual deterioration in retinal diseases such as diabetic retinopathy and retinal vascular occlusion. Dysregulation of junction integrity between endothelial cells by vascular endothelial growth factor (VEGF) was shown to cause retinal vascular hyperpermeability. Accordingly, anti-VEGF agents have been used to treat retinal vascular hyperpermeability. However, they can confer potential toxicity through their deleterious effects on maintenance and survival of neuronal and endothelial cells in the retina. Thus, it is important to identify novel therapeutic targets for retinal vascular hyperpermeability other than VEGF. Here, we prepared murine retinas showing VEGF-induced vascular leakage from superficial retinal vascular plexus and prevention of VEGF-induced leakage by anti-VEGF antibody treatment. We then performed comprehensive proteome profiling of these samples and identified retinal proteins for which abundances were differentially expressed by VEGF, but such alterations were inhibited by anti-VEGF antibody. Functional enrichment and network analyses of these proteins revealed the β2 integrin pathway, which can prevent dysregulation of junction integrity between endothelial cells through cytoskeletal rearrangement, as a potential therapeutic target for retinal vascular hyperpermeability. Finally, we experimentally demonstrated that inhibition of the β2 integrin pathway salvaged VEGF-induced retinal vascular hyperpermeability, supporting its validity as an alternative therapeutic target to anti-VEGF agents.

A Hybrid Discrete-Continuum Mathematical Model of Pattern Prediction in the Developing Retinal Vasculature

Pathological angiogenesis has been extensively explored by the mathematical modelling community over the past few decades, specifically in the contexts of tumour-induced vascularisation and wound healing. However, there have been relatively few attempts to model angiogenesis associated with normal development, despite the availability of animal models with experimentally accessible and highly ordered vascular topologies: for example, growth and development of the vascular plexus layers in the murine retina. The current study aims to address this issue through the development of a hybrid discrete-continuum mathematical model of the developing retinal vasculature in neonatal mice that is closely coupled with an ongoing experimental programme. The model of the functional vasculature is informed by a range of morphological and molecular data obtained over a period of several days, from 6 days prior to birth to approximately 8 days after birth. The spatio-temporal formation of the superficial retinal vascular plexus (RVP) in wild-type mice occurs in a well-defined sequence. Prior to birth, astrocytes migrate from the optic nerve over the surface of the inner retina in response to a chemotactic gradient of PDGF-A, formed at an earlier stage by migrating retinal ganglion cells (RGCs). Astrocytes express a variety of chemotactic and haptotactic proteins, including VEGF and fibronectin (respectively), which subsequently induce endothelial cell sprouting and modulate growth of the RVP. The developing RVP is not an inert structure; however, the vascular bed adapts and remodels in response to a wide variety of metabolic and biomolecular stimuli. The main focus of this investigation is to understand how these interacting cellular, molecular, and metabolic cues regulate RVP growth and formation. In an earlier one-dimensional continuum model of astrocyte and endothelial migration, we showed that the measured frontal velocities of the two cell types could be accurately reproduced by means of a system of five coupled partial differential equations (Aubert et al. in Bull. Math. Biol. 73:2430-2451, 2011). However, this approach was unable to generate spatial information and structural detail for the entire retinal surface. Building upon this earlier work, a more realistic two-dimensional hybrid PDE-discrete model is derived here that tracks the migration of individual astrocytes and endothelial tip cells towards the outer retinal boundary. Blood perfusion is included throughout plexus development and the emergent retinal architectures adapt and remodel in response to various biological factors. The resulting in silico RVP structures are compared with whole-mounted retinal vasculatures at various stages of development, and the agreement is found to be excellent. Having successfully benchmarked the model against wild-type data, the effect of transgenic over-expression of various genes is predicted, based on the ocular-specific expression of VEGF-A during murine development. These results can be used to help inform future experimental investigations of signalling pathways in ocular conditions characterised by aberrant angiogenesis.

Dynamics of angiogenesis during murine retinal development: a coupledin vivoandin silicostudy

The manner in which the superficial retinal vascular plexus (RVP) develops in neonatal wild-type mice is relatively well documented and poses an interesting challenge to the mathematical modelling community. Prior to birth, astrocyte sprouting and proliferation begin around the edge of the optic nerve head, and subsequent astrocyte migration in response to a chemotactic gradient of platelet-derived growth factor (PDGF)-A results in the formation of a dense scaffold on the surface of the inner retina. Astrocytes express a variety of chemotactic and haptotactic proteins that subsequently induce endothelial cell sprouting and modulate growth of the RVP. An experimentally informed, two-dimensional hybrid partial differential equation-discrete model is derived to track the outward migration of individual astrocyte and endothelial tip cells in response to the appropriate biochemical cues. Blood perfusion is included throughout the development of the plexus, and the evolving retinal trees are allowed to adapt and remodel by means of several biological stimuli. The resulting wild-type in silico RVP structures are compared with corresponding experimental whole mounts taken at various stages of development, and agreement between the respective vascular morphologies is found to be excellent. Subsequent numerical predictions help elucidate some of the key biological processes underlying retinal development and demonstrate the potential of the virtual retina for the investigation of various vascular-related diseases of the eye.

Norrin stimulates cell proliferation in the superficial retinal vascular plexus and is pivotal for the recruitment of mural cells

Mutations in Norrin, the ligand of a receptor complex consisting of FZD4, LRP5 and TSPAN12, cause severe developmental blood vessel defects in the retina and progressive loss of the vascular system in the inner ear, which lead to congenital blindness and progressive hearing loss, respectively. We now examined molecular pathways involved in developmental retinal angiogenesis in a mouse model for Norrie disease. Comparison of morphometric parameters of the superficial retinal vascular plexus (SRVP), including the number of filopodia, vascular density and number of branch points together with inhibition of Notch signaling by using DAPT, suggest no direct link between Norrin and Notch signaling during formation of the SRVP. We noticed extensive vessel crossing within the SRVP, which might be a loss of Wnt- and MAP kinase-characteristic feature. In addition, endomucin was identified as a marker for central filopodia, which were aligned in a thorn-like fashion at P9 in Norrin knockout (Ndp(y/-)) mice. We also observed elevated mural cell coverage in the SRVP of Ndp(y/-) mice and explain it by an altered expression of PDGFβ and its receptor (PDGFRβ). In vivo cell proliferation assays revealed a reduced proliferation rate of isolectin B4-positive cells in the SRVP from Ndp(y/-) mice at postnatal day 6 and a decreased mitogenic activity of mutant compared with the wild-type Norrin. Our results suggest that the delayed outgrowth of the SRVP and decreased angiogenic sprouting in Ndp(y/-) mice are direct effects of the reduced proliferation of endothelial cells from the SRVP.

Chronic systemic hypoxia causes intra‐retinal angiogenesis

Retinal hypoxia occurs in many conditions that cause vascular disease in the eye and is an important stimulus to new vessel formation. However, the adult retina can also become hypoxic when there is systemic hypoxaemia such as occurs in chronic lung diseases, congenital cardiac disease and residence at high altitude. Little is known about the adaptive responses of the retinal vasculature in such circumstances. Previous research in the retinopathy of prematurity model may not apply to the adult tissue given the different mechanisms controlling angiogenesis in developing and mature circulations. We tested the hypothesis that chronic systemic hypoxia leads to angiogenesis in the adult retinal circulation, in the absence of pre-existing vascular disease. Adult male Sprague-Dawley rats (n=9) were exposed to a fraction of inspired oxygen of 0.10 for 2 weeks while control animals (n=10) were exposed to room air. Stereological techniques were used to quantify the vascular volume, endothelial surface area and the total number of branch points of all blood vessels in the superficial retinal vascular plexus. The mean volume and endothelial surface area of these vessels were significantly greater in the hypoxic than in the control group. The mean number of blood vessel branch points was also significantly greater in the hypoxic group. Our findings demonstrate that chronic systemic hypoxia, in the absence of other pathological processes, causes angiogenesis in the adult rat retina and provide an in vivo model for investigating this important process in the adult retina, in particular pathways specific to this tissue.