Search

To describe a case of inflammatory neovascularization of the lens after open globe injury., Case report., A 57-year-old man presented with severe inflammation, posterior synechiae with traumatic cataract, and thick neovascularization of the intralenticular and anterior lens capsule after open globe injury in the left eye. We administered an intravitreal bevacizumab injection and performed cataract surgery with synechiolysis 1 month later., Inflammation after open globe injury may present as intralenticular neovascularization. Before cataract surgery for traumatic cataract with intralenticular neovascularization, the use of intravitreal bevacizumab injection was ineffective.

The plasma membranes of the human lens fiber cell are overloaded with cholesterol that not only saturates the phospholipid bilayer of these membranes but also leads to the formation of pure cholesterol bilayer domains. Cholesterol level increases with age, and for older persons, it exceeds the cholesterol solubility threshold, leading to the formation of cholesterol crystals. All these changes occur in the normal lens without too much compromise to lens transparency. If the cholesterol content in the cell membranes of other organs increases to extent where cholesterol crystals forma, a pathological condition begins. In arterial cells, minute cholesterol crystals activate inflammasomes, induce inflammation, and cause atherosclerosis development. In this review, we will indicate possible factors that distinguish between beneficial and negative cholesterol action, limiting cholesterol actions to those performed through cholesterol in cell membranes and by cholesterol crystals.

There exists a large body of research on the lens of the mammalian eye over the past several decades. The objective of this work is to provide a link between the most recent computational models and some of the pioneering work in the 1970s and 80s. We introduce a general nonelectroneutral model to study the microcirculation in the lens of the eye. It describes the steady-state relationships among ion fluxes, between water flow and electric field inside cells, and in the narrow extracellular spaces between cells in the lens. Using asymptotic analysis, we derive a simplified model based on physiological data and compare our results with those in the literature. We show that our simplified model can be reduced further to the first-generation models, whereas our full model is consistent with the most recent computational models. In addition, our simplified model captures in its equations the main features of the full computational models. Our results serve as a useful link intermediate between the computational models and the first-generation analytical models. Simplified models of this sort may be particularly helpful as the roles of similar osmotic pumps of microcirculation are examined in other tissues with narrow extracellular spaces, such as cardiac and skeletal muscle, liver, kidney, epithelia in general, and the narrow extracellular spaces of the central nervous system, the "brain." Simplified models may reveal the general functional plan of these systems before full computational models become feasible and specific., (Copyright © 2019 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

It has been proposed that optical properties of the lens are actively maintained by an internal microcirculation system that utilizes ionic and fluid fluxes to deliver nutrients to deeper regions of the lens tissue via the extracellular space faster than would occur by passive diffusion alone. To test this hypothesis, we utilized a range of commercially available magnetic resonance imaging (MRI) reagents of varying molecular sizes that served as tracers of extracellular solute delivery. The penetration of these tracers into bovine lenses incubated in the absence and presence of solutions that inhibit the microcirculation was monitored in real time over a 4-h period using T1-weighted MRI. We found that only the smaller contrast agents were delivered to the core of the lens and that the rate of solute penetration was significantly faster than that calculated simple diffusion. Next, the lenses were first incubated in either high extracellular K + to depolarize the lens potential or ouabain to inhibit the Na + pump. These two perturbations are known to inhibit the circulating ionic and fluid fluxes that are proposed to drive solute delivery into the lens core. Both perturbations inhibited the delivery of the extracellular tracer molecules to the lens core. Our findings suggest that the microcirculation system can potentially be harnessed to deliver exogenous antioxidants to the lens core to afford mature fiber cells protection against oxidative damage that ultimately manifests as age-related nuclear cataract.

The superficial ocular vasculature of the embryonic zebrafish develops in a highly stereotypic manner and hence provides a convenient model for studying molecular mechanisms that regulate vascular patterning. We have used transgenic zebrafish embryos in which all endothelial cells express enhanced Green Fluorescent Protein and small molecule inhibitors to examine the contribution of two signaling pathways, vascular endothelial growth factor (VEGF) and Hedgehog (Hh) pathways, to the development of the superficial system. We find that most, but not all vessels of the superficial system depend on VEGF signaling for their growth. Hh signaling appears to limit superficial vessel growth over the dorsal eye and is required to promote superficial vessel growth over the ventral eye. These effects of Hh signaling are indirect. Our initial analyses of factors that regulate growth and patterning of superficial ocular vessels suggest that early patterning events in the embryo during organogenesis stages could influence vascular patterning later on. By studying development of specific vascular systems it should be possible to identify new roles for signaling pathways in regulating vascular development.

Our sense of vision is critically dependent on the clarity of the crystalline lens. The most common cause of transparency loss in the lens is age-related nuclear cataract, which is due to accumulative oxidative damage to this tissue. Since the ocular lens is an avascular tissue, it has to maintain its physiological homeostasis and antioxidant levels using a system of water microcirculation. This system has been experimentally imaged in animal lenses using different modalities. Based on these data, computational models have been developed to predict the properties of this system in human lenses and its changes due to aging. Although successful in predicting many aspects of lens fluid dynamics, at least in animal models, these in-silica models still need further improvement to become more accurate and representative of human ocular lens. We have been working on gathering experimental data and simultaneously developing computational models of lens microcirculation for the past decade. This review chronologically looks at the development of data-driven computational foundations of lens microcirculation model, its current state, and future advancement directions. A comprehensive model of lens fluid dynamics is essential to understand the physiological optics of this tissue and ultimately the underlying mechanisms of cataract onset and progression.

A 17-month-old girl referred for a suspected ciliary body medulloepithelioma was found to have persistent fetal vasculature. Fluorescein angiography showed perfused hyaloid artery posterior tunica vasculosa lentis with brittle star appearance and nonperfused anterior pupillary membrane. Ultrasound biomicroscopy confirmed absence of iris or ciliary body solid tumor., (Copyright 2014, SLACK Incorporated.)

Purpose: To investigate presence of remnants of the tunica vasculosa lentis, a possible indication of anterior segment dysgenesis, in subjects with the long anterior zonule (LAZ) trait., Methods: Retroillumination photographs of the pupil region had been collected in earlier study of the LAZ trait in African Americans. Secondary image analysis was performed to assess the frequency of intact persistent pupillary membrane iris strands (PPMIS)., Results: The analysis included 148 subjects, comprised of 74 LAZ subjects (median age=70 y; range, 50 to 91 y; 64 females) and 74 controls (68 y; 50 to 83 y; 64 females). While controlling for age and sex, analysis showed that LAZ subjects were 3.1 times more likely than controls (odds ratio=3.1; 95% confidence interval, 1.4-6.7; P=0.004) to exhibit PPMIS in at least one of their eyes., Conclusion: The LAZ trait, which is being studied as a potential risk factor for glaucoma, was associated with presence of PPMIS in our study population.

Corneal avascularity is important for optical clarity and normal vision. However, the molecular mechanisms that prevent angioblast migration and vascularization of the developing cornea are not clear. Previously we showed that periocular angioblasts and forming ocular blood vessels avoid the presumptive cornea despite dynamic ingression of neural crest cells. In the current study, we investigate the role of Semaphorin3A (Sema3A), a cell guidance chemorepellent, on angioblast migration and corneal avascularity during development. We show that Sema3A, Vegf, and Nrp1 are expressed in the anterior eye during cornea development. Sema3A mRNA transcripts are expressed at significantly higher levels than Vegf in the lens that is positioned adjacent to the presumptive cornea. Blockade of Sema3A signaling via lens removal or injection of a synthetic Sema3A inhibitor causes ectopic migration of angioblasts into the cornea and results in its subsequent vascularization. In addition, using bead implantation, we demonstrate that exogenous Sema3A protein inhibits Vegf-induced vascularization of the cornea. In agreement with these findings, loss of Sema/Nrp1 signaling in Nrp1(Sema-) mutant mice results in ectopic angioblasts and vascularization of the embryonic mouse corneas. Altogether, our results reveal Sema3A signaling as an important cue during the establishment of corneal avascularity in both chick and mouse embryos. Our study introduces cornea development as a new model for studying the mechanisms involved in vascular patterning during embryogenesis and it also provides new insights into therapeutic potential for Sema3A in neovascular diseases., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Case Report: A 72 year-old woman referred for cataract surgery in her right eye. Biomicroscopy revealed a retrocapsular fibrotic tissue in communication with the optic nerve, suggesting a persistent hyaloid artery (PAH). A posterior capsule rupture unexpectedly occurred during lens hydrodissection. One day after surgery, fundus examination showed a combined central retinal artery and vein occlusion., Conclusion: PAH is uncommon, but its presence may alert us of this possible complication during cataract surgery., (Copyright © 2012 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.)

Background: In a previous study (Vaghefi et al. 2012) we described a 3D computer model that used finite element modeling to capture the structure and function of the ocular lens. This model accurately predicted the steady state properties of the lens including the circulating ionic and fluid fluxes that are believed to underpin the lens internal microcirculation system. In the absence of a blood supply, this system brings nutrients to the core of the lens and removes waste products faster than would be achieved by passive diffusion alone. Here we test the predictive properties of our model by investigating whether it can accurately mimic the experimentally measured changes to lens steady-state properties induced by either depolarising the lens potential or reducing Na+ pump rate., Methods: To mimic experimental manipulations reported in the literature, the boundary conditions of the model were progressively altered and the model resolved for each new set of conditions. Depolarisation of lens potential was implemented by increasing the extracellular [K+], while inhibition of the Na+ pump was stimulated by utilising the inherent temperature sensitivity of the pump and changing the temperature at which the model was solved., Results: Our model correctly predicted that increasing extracellular [K+] depolarizes the lens potential, reducing and then reversing the magnitude of net current densities around the lens. While lowering the temperature reduced Na+ pump activity and caused a reduction in circulating current, it had a minimal effect on the lens potential, a result consistent with published experimental data., Conclusion: We have shown that our model is capable of accurately simulating the effects of two known experimental manipulations on lens steady-state properties. Our results suggest that the model will be a valuable predictive tool to support ongoing studies of lens structure and function.

Purpose: 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., Methods: 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, ~20 days of age, and again at 30 and 64 days 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)., Results: In the youngest ROP rats, the TVL was dense, while in RAR rats, it was relatively sparse. By 30 days, 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., Conclusions: 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.

The authors describe a preterm infant who developed advanced retinopathy of prematurity bilaterally with a prominent tunica vasculosa lentis. Treatment with intravitreal bevacizumab resulted in regression of the tunica vasculosa lentis and posterior manifestations of the retinopathy of prematurity. RetCam imaging (Clarity Medical Systems, Pleasanton, CA) of the anterior segment was used to document the dramatic tunica vasculosa lentis resolution., (Copyright 2013, SLACK Incorporated.)

Purpose: The mode of development of the human hyaloid vascular system (HVS) remains unclear. Early studies suggested that these blood vessels formed by vasculogenesis, while the current concept seems to favor angiogenesis as the mode of development. We examined embryonic and fetal human HVS using a variety of techniques to gain new insights into formation of this vasculature., Methods: Embryonic and fetal human eyes from 5.5 to 12 weeks gestation (WG) were prepared for immunohistochemical analysis or for light and electron microscopy. Immunolabeling of sections with a panel of antibodies directed at growth factors, transcription factors, and hematopoietic stem cell markers was employed., Results: Light microscopic examination revealed free blood islands (BI) in the embryonic vitreous cavity (5.5-7 WG). Giemsa stain revealed that BI were aggregates of mesenchymal cells and primitive nucleated erythroblasts. Free cells were also observed. Immunolabeling demonstrated that BI were composed of mesenchymal cells that expressed hemangioblast markers (CD31, CD34, C-kit, CXCR4, Runx1, and VEGFR2), erythroblasts that expressed embryonic hemoglobin (Hb-ε), and cells that expressed both. Few cells were proliferating as determined by lack of Ki67 antigen. As development progressed (12 WG), blood vessels became more mature structurally with pericyte investment and basement membrane formation. Concomitantly, Hb-ε and CXCR4 expression was down-regulated and von Willebrand factor expression was increased with the formation of Weibel-Palade bodies., Conclusions: Our results support the view that the human HVS, like the choriocapillaris, develops by hemo-vasculogenesis, the process by which vasculogenesis, erythropoiesis, and hematopoiesis occur simultaneously from common precursors, hemangioblasts.

Background: It has been proposed that in the absence of a blood supply, the ocular lens operates an internal microcirculation system. This system delivers nutrients, removes waste products and maintains ionic homeostasis in the lens. The microcirculation is generated by spatial differences in membrane transport properties; and previously has been modelled by an equivalent electrical circuit and solved analytically. While effective, this approach did not fully account for all the anatomical and functional complexities of the lens. To encapsulate these complexities we have created a 3D finite element computer model of the lens., Methods: Initially, we created an anatomically-correct representative mesh of the lens. We then implemented the Stokes and advective Nernst-Plank equations, in order to model the water and ion fluxes respectively. Next we complemented the model with experimentally-measured surface ionic concentrations as boundary conditions and solved it., Results: Our model calculated the standing ionic concentrations and electrical potential gradients in the lens. Furthermore, it generated vector maps of intra- and extracellular space ion and water fluxes that are proposed to circulate throughout the lens. These fields have only been measured on the surface of the lens and our calculations are the first 3D representation of their direction and magnitude in the lens., Conclusion: Values for steady state standing fields for concentration and electrical potential plus ionic and fluid fluxes calculated by our model exhibited broad agreement with observed experimental values. Our model of lens function represents a platform to integrate new experimental data as they emerge and assist us to understand how the integrated structure and function of the lens contributes to the maintenance of its transparency.

Objective: To determine if ocular and skin autofluorescence, reflecting advanced glycation end-products, and vascular stiffness correlate in non-diabetic and Type 1 diabetic subjects and if levels differ by diabetes status., Research Design and Methods: Patients with Type 1 diabetes (n = 69, 19 with and 50 without vascular complications) and 60 subjects without diabetes (control) had ocular and skin autofluorescence and pulse-wave analysis performed in the fasted state. Correlations between measures within groups used the Pearson or Spearman correlation-coefficient and measures between groups were compared by ANOVA., Results: Lens and skin autofluorescence correlated in control (r = 0.58, P = 0.0001) and in Type 1 diabetes (r = 0.53, P = 0.001). Corneal autofluorescence correlated with lens (r = 0.53, r = 0.52, P = 0.0001) and skin autofluorescence (r = 0.34, P = 0.01 and r = 0.49, P = 0.00001) in control and Type 1 diabetes respectively. In Type 1 diabetes, small and large artery elasticity correlated inversely and systemic vascular resistance correlated positively with skin autofluorescence (all P = 0.001), and with lens and corneal autofluorescence (all P < 0.03). In Type 1 diabetes tissue advanced glycation end-products correlated with C-reactive protein and inversely with the estimated glucose disposal rate and with circulating advanced glycation end-product levels. Relative to non-diabetic subjects, lens, corneal and skin fluorescence were increased (all P < 0.001) and small artery elasticity was decreased in diabetes (P = 0.04). Lens, corneal and skin autofluorescence were greater (all P = 0.0001) in patients with Type 1 diabetes with complications compared to those without complications, but small artery elasticity did not differ significantly., Conclusions: Ocular and skin autofluorescence and vascular stiffness correlate in non-diabetic and Type 1 diabetes subjects and are increased in Type 1 diabetes. Tissue advanced glycation end-products correlate with vascular risk factors, including circulating advanced glycation end-products., (© 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.)

Background: Neovascularization can occur in various ocular structures including the retina, iris, anterior chamber angle and cornea; however, it rarely occurs in the crystalline lens. Neovascularization results secondary to hypoxic conditions within the eye. A natural balance of angiogenic and antiangiogenic factors are critical for the eye to prevent the formation of neovascularization. Various factors can upset this natural balance, resulting in angiogenesis. Due to the lack of an intrinsic blood supply, intralenticular neovascularization is rare., Case Report: A 61-year-old black male presented with a previous diagnosis of proliferative diabetic retinopathy (PDR). His ocular history included cataract extraction in the left eye (OS) and tractional retinal detachment in both eyes that was surgically repaired OS. His entering visual acuities were NLP OD and 20/400 OS. Upon biomicroscopic evaluation OD, there was evidence of a hypermature cataract with iris neovascularization and neovascularization coursing over and within the anterior capsule of the lens., Conclusions: Intralenticular neovascularization is a rarely reported ocular complication. We present a patient with uncontrolled diabetes resulting in proliferative diabetic retinopathy, extreme ocular ischemia, and consequent intralenticular neovascularization., (American Optometric Association.)

Purpose: To report a series of cases involving neovascularization within the human crystalline lens-a normally avascular structure-after ocular trauma. This is a retrospective, consecutive observational case series with review of the prevailing literature., Methods: Four individuals with a history of ocular trauma and subsequent cataract development were examined between May 2004 and April 2007. All had hypermature cataracts and intraocular inflammation, presumably secondary to phacolysis; two of the four had concurrent hyphema and ocular hypertension in the involved eye., Results: All subjects in this series were found to display a discrete network of blood vessels within the structure of the crystalline lens, just beneath the anterior lens capsule., Conclusions: Neovascularization of the crystalline lens has received little attention in the ophthalmic literature, having been described only rarely in individual case reports. This manuscript details the first known case series involving lenticular neovascularization, and offers insight into its possible developmental mechanism.

Purpose: The hyaloid vascular system (HVS) is a transient network nourishing developing eyes and has been widely used as a natural model to study blood vessel regression. Failure of its regression in humans leads to several blinding diseases. Lymphatic vessel endothelial hyaluronic acid receptor (LYVE-1) is a recently defined lymphatic marker that is also expressed by a subpopulation of macrophages. To date, there is no report on its expression in the HVS. This study was conducted to investigate whether LYVE-1 is expressed in the HVS and how it is associated with the vascular structure and macrophage phenotype., Methods: Normal C57BL/6 mouse eyeballs were sampled from embryonic day (E) 10.5 to postnatal (P) and adult stages for immunofluorescent microscopic studies with antibodies against LYVE-1, CD31 (panendothelial cell marker), and F4/80 (macrophage marker). Additionally, Angiopoietin-2 (Ang-2) knockout mice with abnormally persistent HVS were examined., Results: The LYVE-1 expression was detected on normal HVS between E12.5 and P14. The LYVE-1(+) cells were F4/80(+) but CD31(-), indicating a macrophage lineage. Additionally, LYVE-1(+) cells bud on CD31(+) vessels and constitute an integral part of the network in both normal developing and Ang-2 knockout mice., Conclusions: This study provides the first evidence that the HVS contains a LYVE-1(+) cellular component in both physiological and pathologic conditions. This novel finding not only provides a new concept in defining the embryogenesis and pathogenesis of the HVS, it also leads to a completely natural model in which to study the functions of the LYVE-1 pathway, an important topic for lymphatic research as well.

An 8-month-old boy was found to have unilateral persistent fetal vasculature (PFV) and a small visually insignificant lens opacity. No changes were noted in the appearance of the eye on examinations up to age 3 years. At the age of 4 years, a posterior lentiglobus requiring surgical intervention developed. The thinned and bulging posterior capsule ruptured at surgery. PFV, when treated conservatively, has not been reported to lead to progressive lentiglobus. This case documents the rare concurrence of PFV and lentiglobus., (Copyright (c) 2010 American Association for Pediatric Ophthalmology and Strabismus. Published by Mosby, Inc. All rights reserved.)

The cells of most mammalian organs are connected by groups of cell-to-cell channels called gap junctions. Gap junction channels are made from the connexin (Cx) family of proteins. There are at least 20 isoforms of connexins, and most tissues express more than 1 isoform. The lens is no exception, as it expresses three isoforms: Cx43, Cx46, and Cx50. A common role for all gap junctions, regardless of their Cx composition, is to provide a conduit for ion flow between cells, thus creating a syncytial tissue with regard to intracellular voltage and ion concentrations. Given this rather simple role of gap junctions, a persistent question has been: Why are there so many Cx isoforms and why do tissues express more than one isoform? Recent studies of lens Cx knockout (KO) and knock in (KI) lenses have begun to answer these questions. To understand these roles, one must first understand the physiological requirements of the lens. We therefore first review the development and structure of the lens, its numerous transport systems, how these systems are integrated to generate the lens circulation, the roles of the circulation in lens homeostasis, and finally the roles of lens connexins in growth, development, and the lens circulation.

Purpose: Alterations in FOXC1 dosage lead to a spectrum of highly penetrant, ocular anterior segment dysgenesis phenotypes. The most serious outcome is the development of glaucoma, which occurs in 50% to 75% of patients. Therefore, the need to identify specific pathways and genes that interact with FOXC1 to promote glaucoma is great. In this study, the authors investigated the loss of foxC1 in the zebrafish to characterize phenotypes and gene interactions that may impact glaucoma pathogenesis., Methods: Morpholino knockdown in zebrafish, RNA and protein marker analyses, transgenic reporter lines, and angiography, along with histology and transmission electron microscopy, were used to study foxC1 function and gene interactions., Results: Zebrafish foxC1 genes were expressed dynamically in the developing vasculature and periocular mesenchyme during development. Multiple ocular and vascular defects were found after the knockdown of foxC1. Defects in the hyaloid vasculature, arteriovenous malformations, and coarctation of the aorta were observed with maximal depletion of foxC1. Partial loss of foxC1 resulted in CNS and ocular hemorrhages, defects in intersegmental vessel patterning, and increased vascular permeability. To investigate the basis for these disruptions, the ultrastructure of foxC1-depleted hyaloid vascular cells was studied. These experiments, along with laminin-111 immunoreactivity, revealed disruptions in basement membrane integrity. Finally, codepletion of laminin alpha-1 and foxC1 uncovered a genetic interaction between these genes during development., Conclusions: Genetic interactions between FOXC1 and basement membrane components influence vascular stability and may impact glaucoma development and increase stroke risk in FOXC1 patients.

The sense of vision requires that light penetrate through the ocular lens. Experiments, performed and published by many research groups, have suggested that the lens, which has no blood vessels, relies on internally directed ion and water fluxes for its circulation, survival and transparency. We investigated the internal diffusive pathways of the lens in order to better understand the constraints that may be operating on directional lens fluxes. Small animal magnetic resonance imaging, including T2-weighted and diffusion tensor imaging, was used to measure tissue properties and diffusivity throughout cultured bovine lenses. A range of concentric regions of signal intensity was distinguished inside the lens, by both T2-weighted signal and mean diffusivity. Diffusivity mapping of the lens revealed novel anisotropic polar and equatorial zones of pronounced diffusivity directed transverse to the fiber cells. In contrast, an inner zone including the lens nucleus showed isotropic and weak diffusivity. Our results lend support to models of internally directed lens micro-circulation, by placing non-structural diffusive constraints on global patterns of fluid circulation.

Background: The Dbl family of proteins represents a large group of proto-oncogenes involved in cell growth regulation. The numerous domains that are present in many Dbl family proteins suggest that they act to integrate multiple inputs in complicated signaling networks involving the Rho GTPases. Alterations of the normal function of these proteins lead to pathological processes such as developmental disorders and neoplastic transformation. We generated transgenic mice introducing the cDNA of Dbl oncogene linked to the metallothionein promoter into the germ line of FVB mice and found that onco-Dbl expression in mouse lenses affected proliferation, migration and differentiation of lens epithelial cells., Results: We used high density oligonucleotide microarray to define the transcriptional profile induced by Dbl in the lenses of 2 days, 2 weeks, and 6 weeks old transgenic mice. We observed modulation of genes encoding proteins promoting epithelial-mesenchymal transition (EMT), such as down-regulation of epithelial cell markers and up-regulation of fibroblast markers. Genes encoding proteins involved in the positive regulation of apoptosis were markedly down regulated while anti-apoptotic genes were strongly up-regulated. Finally, several genes encoding proteins involved in the process of angiogenesis were up-regulated. These observations were validated by histological and immunohistochemical examination of the transgenic lenses where vascularization can be readily observed., Conclusion: Onco-Dbl expression in mouse lens correlated with modulation of genes involved in the regulation of EMT, apoptosis and vasculogenesis leading to disruption of the lens architecture, epithelial cell proliferation, and aberrant angiogenesis. We conclude that onco-Dbl has a potentially important, previously unreported, capacity to dramatically alter epithelial cell migration, replication, polarization and differentiation and to induce vascularization of an epithelial tissue.

Cited2 is a transcriptional modulator with pivotal roles in different biological processes. Cited2-deficient mouse embryos manifested two major defects in the developing eye. An abnormal corneal-lenticular stalk was characteristic of Cited2(-/-) developing eyes, a feature reminiscent of Peters' anomaly, which can be rescued by increased Pax6 gene dosage in Cited2(-/-) embryonic eyes. In addition, the hyaloid vascular system showed hyaloid hypercellularity consisting of aberrant vasculature, which might be correlated with increased VEGF expression in the lens. Deletion of Hif1a (which encodes HIF-1alpha) in Cited2(-/-) lens specifically eliminated the excessive accumulation of cellular mass and aberrant vasculature in the developing vitreous without affecting the corneal-lenticular stalk phenotype. These in vivo data demonstrate for the first time dual functions for Cited2: one upstream of, or together with, Pax6 in lens morphogenesis; and another in the normal formation of the hyaloid vasculature through its negative modulation of HIF-1 signaling. Taken together, our study provides novel mechanistic revelation for lens morphogenesis and hyaloid vasculature formation and hence might offer new insights into the etiology of Peters' anomaly and ocular hypervascularity.

The authors report an unusual case of persistent tunica vasculosa lentis in a patient with minimal retinopathy of prematurity (ROP). A 3-month-old male infant who had been born at 31 weeks' gestation presented with a significant amount of persistent tunica vasculosa lentis and arteriolar tortuosity with minimal ROP and no plus disease. After weekly observation and no surgical intervention, the arteriolar tortuosity lessened but the tunica vasculosa lentis persisted. Persistent tunica vasculosa lentis can be mistaken for iris vascular engorgement, suggesting plus disease and high-risk prethreshold ROP. Differentiation between tunica vasculosa lentis and iris vascular engorgement, as well as correct diagnosis of plus disease, is critical when considering laser treatment for high-risk prethreshold ROP.

The lens and cornea are transparent and usually avascular. Controlling nutrient supply while maintaining transparency is a physiological challenge for both tissues. During sleep and with contact lens wear the endothelial layer of the cornea may become hypoxic, compromising its ability to maintain corneal transparency. The mechanism responsible for establishing the avascular nature of the corneal stroma is unknown. In several pathological conditions, the stroma can be invaded by abnormal, leaky vessels, leading to opacification. Several molecules that are likely to help maintain the avascular nature of the corneal stroma have been identified, although their relative contributions remain to be demonstrated. The mammalian lens is surrounded by capillaries early in life. After the fetal vasculature regresses, the lens resides in a hypoxic environment. Hypoxia is likely to be required to maintain lens transparency. The vitreous body may help to maintain the low oxygen level around the lens. The hypothesis is presented that many aspects of the aging of the lens, including increased hardening, loss of accommodation (presbyopia), and opacification of the lens nucleus, are caused by exposure to oxygen. Testing this hypothesis may lead to prevention for nuclear cataract and insight into the mechanisms of lens aging. Although they are both transparent, corneal pathology is associated with an insufficient supply of oxygen, while lens pathology may involve excessive exposure to oxygen.

The structure of adult human vitreous condensations (tractus, membranelles) corresponds to the structure of obliterated embryonal vasa hyaloidea. Some embryonal hyaloidal vessels and structures extend from the tunica vasculosa lentis and attach to the retina between the equator and ora serrata. In normal fetal development, these hyaloidal vessels and structures successively disappear because of apoptosis. The lower the birth weight of a premature infant, the higher the risk of retinopathy of prematurity (ROP) due to the disproportion between the regression of vasa hyaloidea (hyaloideoretinal adherences) and the proliferation of retinal vessels. This may be caused by an enhanced growth of retinal vessels (or a delayed regression of vasa hyaloidea). The growth of retinal vessels stops at a barrier formed by the retina-attaching hyaloidal remnants (vessels), resulting in a demarcation line and ROP. The same retinal vessels may then, as a fibrovascular tissue, overgrow the remnants of retina-attaching hyaloidal structures (as guiding formations) through the vitreous cavity up to the tunica vasculosa lentis. The process may result in the progression from ROP stage 2 to ROP stage 5., ((c) 2008 S. Karger AG, Basel.)

The persistence of the fetal vascular system is a rare ocular malformation whose origin remains unknown. It comprises a group of complex ocular malformations from which the various clinical forms have a heterogeneous functional prognosis. The diagnosis depends on a precise and complete examination of the child's eye, often under general anesthesia. Various clinical forms can be found together, ranging from the tiny form with no visual repercussion or ocular or systemic anomaly associated with the major forms involving the totality of the ocular structures and systemic syndromes. A systematic general pediatric examination is therefore recommended. The treatment is adapted individually for early and specific surgical and medical treatment. In the event of intervention, the induced aphakia will be corrected in one procedure with an implantation, generally sutured with the sclera, or at the time of a second intervention after the wearing of glasses or a contact lens. However, the complications can sometimes lead to rapid phthisis bulbi. Whatever solution is chosen, the final functional result has progressed thanks to early diagnosis, the surgical techniques suggested, even if implantation continues to be debated. Amblyopia must be treated for the entire sensitive period. However, despite good rehabilitation, the average functional prognosis remains disappointing, probably because of the overall ocular malformation.

The eye is considered to be a critical organ when determining safety standards for radiofrequency radiation. With a detailed anatomy of the human eye and orbit inserted in a whole-head model, the specific absorption rates (SARs) and thermal effects were determined under exposure to a dipole antenna representing a mobile phone operating at 900, 1500 and 1800 MHz with an output power of 1 W. The temperature rise was calculated by taking the blood flow into account either by the Pennes bioheat model or by including the discrete vasculature (DIVA). In addition, a simple spherical model using constant heat transfer coefficients was used. Peak SARs in the humour are 4.5, 7.7 and 8.4 W kg(-1) for 900, 1500 and 1800 MHz respectively. Averaged over the whole eyeball, the SARs are 1.7, 2.5 and 2.2 W kg(-1). The maximum temperature rises in the eye due to the exposure are 0.22, 0.27 and 0.25 degrees C for exposure of 900, 1500 and 1800 MHz, respectively, calculated with DIVA. For the Pennes bioheat model, the temperature rises are slightly lower: 0.19, 0.24, 0.22 degrees C respectively. For the simple spherical model, the maximum temperature rises are 0.15, 0.22 and 0.20 degrees C. The peak temperature is located in the anterior part of the lens for 900 MHz and deeper in the eye for higher frequencies, and in the posterior part of the lens for 1500 MHz and close to the centre of the eyeball for 1800 MHz. For these RF safety applications, both DIVA and the Pennes bioheat model could be used to relate the SAR distributions to the resulting temperature distributions. Even though, for these artificial exposure conditions, the SAR values are not in compliance with safety guidelines, the maximum temperature rises in the eye are too small to give harmful effects. The temperature in the eye also remains below body core temperature.

The lens is the largest organ in the body that lacks a vasculature. The reason is simple: blood vessels scatter and absorb light while the physiological role of the lens is to be transparent so it can assist the cornea in focusing light on the retina. We hypothesize this lack of blood supply has led the lens to evolve an internal circulation of ions that is coupled to fluid movement, thus creating an internal micro-circulatory system, which makes up for the lack of vasculature. This review covers the membrane transport systems that are believed to generate and direct this internal circulatory system.

Thrombospondin-1 (TSP1) is an endogenous inhibitor of angiogenesis and induces endothelial cell (EC) apoptosis. To study the role TSP1 plays during vascular development and neovascularization, we assessed the effects of ectopic TSP1 expression in the lens on retinal vascularization in transgenic mice. The TSP1 over-expressing mice showed abnormalities in the development of retinal vasculature. There was a dramatic decrease in the density of superficial and deep vascular plexuses of the retina in transgenic mice. The retinal vessels in TSP1 transgenic mice also appeared nonuniform and abnormal in maturation. We detected an increase in the number of EC undergoing apoptosis, which was compensated, in part, by an increase in cell proliferation in retinal vasculature of TSP1 transgenic mice. The TSP1 transgenic mice also exhibited increased levels of vessel obliteration and a limited preretinal neovascularization during oxygen-induced ischemic retinopathy (OIR). Our results indicate increased expression of TSP1 attenuates normal retinal vascularization and preretinal neovascularization during OIR. Therefore, modulation of TSP1 expression may provide an effective mechanism for regulation of ocular angiogenesis., ((c) 2006 Wiley-Liss, Inc.)

Formation of a correctly organised vasculature and subsequently embryonic survival is critically dependent on the dosage and site-specific expression of VEGF. Murine VEGF exists in three common isoforms (viz. 120, 164 and 188 amino acids) having different organ specific distribution levels. Gene knock-in studies show that expression of any of the individual isoforms of VEGF extends survival until birth, although each is associated with distinct organ-specific abnormalities. Comparison of the effects of VEGF isoform expression is complicated by the general lethality of mis-expression, in addition to cumulative effects of adjacent tissues from the inappropriately patterned vasculature. Here we investigate the effects of over-expression of individual VEGFA isoforms from the lens-specific alphaA-Crystallin promoter and characterise their effects on the vessel morphology of the hyaloid and developing retinal vasculature. Since the hyaloid vasculature is an anatomically distinct, transient vasculature of the eye, comprising 3 cell types (endothelium, pericytes and macrophages) it is possible to more readily interpret the role of individual VEGF-A isoforms in vascular pattern formation in this model. The severity of the vascular phenotype, characterised by a hyperplastic hyaloid at E13.5 and subsequently retinal vascular patterning and ocular defects, is most severe in transgenics over-expressing the more diffusible forms of VEGFA (120 and 164), whereas in VEGFA(188) transgenics the hyaloid vascular defects partially resolve post-natally. The results of this study indicate that individual isoforms of VEGFA induce distinct vascular phenotypes in the eye during embryonic development and that their relative doses provide instructive cues for vascular patterning.

The arterial supply to the retina and lens of 10 fetal, 10 neonatal and four adult Zavot-bred cattle of both sexes was studied macroscopically and by stereoscopic microscopy by means of vascular perfusion with latex, giving special emphasis on the hyaloid artery. The central retinal artery ramified in four major retinal arterioles, which formed a compact network throughout the retina (holangiotic or euangiotic pattern). The hyaloid artery was patent in all fetal stages and extended through the vitreous cavity of the eye to the caudal surface of the capsule of the lens. Atrophy of the hyaloid artery began immediately after birth and was completed on day 17 after parturition. No remnant of the hyaloid artery in the vitreous cavity was observed in the adult cattle examined at stereoscopic microscopic level.

Purpose: Ultrasound biomicroscopy (UBM) utilizes frequencies higher than conventional diagnostic ultrasound and can noninvasively provide anatomic and functional information about mouse ocular structures in vivo at high resolution. Vascular development can also be assessed with high-frequency Doppler imaging, which permits detection and characterization of ocular blood flow not detectable at lower, conventional Doppler frequencies., Methods: The eyes of CD-1 mice were examined daily from the day of birth to postnatal day (P)16. Hyaloid vascular system anatomy was imaged with UBM and microcomputed tomography (microCT). Blood flow velocity was also measured with Doppler UBM imaging in the hyaloid artery, vasa hyaloidea propria, tunica vasculosa lentis, and retina., Results: In the mouse, the hyaloid vasculature degenerated from a well-defined structure at birth by progressive loss of branches. Hyaloid regression coincided with a progressive decrease in blood velocity detected in the hyaloid vascular structures, which is thought to be one of the major triggering factors of the regression in these vessels. At P13, no further blood flow was detected in the CD-1 mouse hyaloid vasculature. An inverse relationship was also shown between peak blood velocity in the lens and retina., Conclusions: UBM imaging provides a valuable means of rapidly and noninvasively characterizing ocular development in vivo. MicroCT scans have also provided intralumenal images of hyaloid vascular structure. This is the first study of vascular structure and function during the dynamic process of hyaloid vascular regression during mouse neonatal eye development and the first three-dimensional images of the complex hyaloid vascular structure.

Background: The ocular fetal vasculature normally regresses by apoptosis but for unknown reasons fails to regress in the human disease persistent fetal vasculature., Objective: To investigate whether proapoptotic Bcl-2 members, Bax and Bak, are involved in fetal vasculature regression., Methods: Adult eyes from mice deficient in Bax and/or Bak were examined grossly and histologically for persistence of fetal vasculature. Vessels were identified by the presence of lumens and erythrocytes and by Factor VIII labeling. Eyes from postnatal day 7 mice were processed for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) analysis to determine if deficiency of Bax and Bak results in defective developmental apoptosis., Results: Only bax(-/-)bak(-/-) eyes retained fetal vasculature into adulthood. This vasculature consisted of a hyaloid artery emerging from the optic nerve head and intravitreal and perilental vessels but not a pupillary membrane. At postnatal day 7, wild-type but not bax(-/-)bak(-/-) eyes had TUNEL-positive cells in the fetal vasculature., Conclusions: These data demonstrate that Bax and Bak serve overlapping functions in fetal vasculature regression, emphasizing the importance of apoptosis in developmental remodeling. Clinical Relevance Disruption of Bax and Bak results in persistent fetal vasculature in knockout mice, providing a model of the human disease persistent fetal vasculature to investigate its etiology and potential therapies.

PHACE Syndrome is a neurocutaneous disease spectrum encompassing the following features: Posterior fossa brain malformations, large facial Hemangiomas, Arterial anomalies, Coarctation of the aorta and cardiac defects, and Eye abnormalities. We report the ocular and systemic findings, as well as the management course, of an infant who has all the characteristic features of PHACE syndrome and also describe what we believe to be the first reported case of this syndrome with Persistent Fetal Vasculature (PFV).

A 3.26-kg neonate with a gestational age of 40 weeks presented with episodic hypothermia and seizures, but stable vital signs. Semilobar holoprosencephaly was seen on magnetic resonance imaging. Ocular examination revealed bilateral persistent fetal vasculature. As genetic testing was not contributory, toxic intrauterine environmental insulin causing neurologic maldevelopment was the presumed etiology.