The role of nitric oxide in physiology and pathogenesis of ocular diseases

Nitric oxide (NO) is a gas with diverse biological activities produced from arginine by nitric oxide synthetase (NOS). The loss of retinal ganglion cells is a hallmark of many ophthalmic diseases including glaucoma, retinal ischemia due to central artery occlusion and anterior ischemic optic neuropathy. It may well be significant in optic neuritis, optic nerve, trauma and AIDS. NO appears to be involved in the regulation of intraocular pressure, in the modulation of ocular blood flow and in apoptosis. This article gives a short and simplified overview of the biochemistry of NO and its role in physiology and pathogenesis of ocular diseases.     

Circadian rhythms in the eye: the physiological significance of melatonin receptors in ocular tissues

Many biological processes display circadian rhythms in activity, which presumably operate to coordinate cellular functions with daily environmental oscillations. The diurnal changes in environmental illumination are conveyed by the retina to the brain to entrain circadian rhythms throughout the body. Many ocular tissues themselves exhibit circadian rhythms of activity to optimize specific processes which require coordination with the light-dark cycle. The circadian signaling molecule, melatonin, is secreted into the circulation from the pineal gland, and is also produced within specific ocular cells such as retinal photoreceptors, ciliary epithelial cells, and perhaps cells of the lens. Melatonin appears to entrain many aspects of the biological clock via activation of specific G-protein-coupled integral membrane melatonin receptors. Melatonin receptors have been identified in many ocular tissues, including the neural retina, retinal pigment epithelium, ciliary body, cornea, sclera, and lens. This review will describe the circadian rhythmicity of some of the functions of these various ocular tissues, and will attempt to correlate these circadian activities with the expression of specific G-protein-coupled melatonin receptors, the role of melatonin in the regulation of circadian activity in ocular tissues, and its potential role in ocular diseases.     

Systemic and Ocular Vascular Roles of the Antiglaucoma Agents b-Adrenergic Antagonists and Ca2+ Entry Blockers

This review addresses whether the antiglaucoma agents β-adrenergic antagonists and Ca²⁺ entry blockers cause vasoactive effects in the retinal and other ocular vasculatures, as they do in other tissues. The potent vasodilating effects of Ca²⁺ entry blockers on ocular vessels have recently been demonstrated in in vivo and in vitro studies, implying that the maintenance of ocular vascular tone relies almost exclusively on extracellular Ca²⁺. Ca²⁺ entry blockers may potentially play a role in relaxing the retinal, long posterior ciliary, and ophthalmociliary arteries to improve the ocular circulation in vascular diseases in which there is considerable vascular tone present. The β-adrenergic antagonists are discussed with reference to their antihypertensive role, their effect on other vascular beds, and finally what is known of their effect in the ocular vasculature. The emerging evidence that particular selective β-adrenergic antagonists, such as betaxolol, are also potent Ca²⁺ channel entry blockers in other vascular beds is presented. Betaxolol has been shown to induce vasodilatation in the retinal and other ocular vascular beds, although studies have shown that β₁-adrenergic receptors are sparse in these vascular beds. This implies that an alternative mechanism must be responsible for betaxolol-induced vasodilatation. Evidence is presented that betaxolol vasodilates via its potent Ca²⁺ channel entry blocking properties, and its potency and ability to vasodilate are compared with those of nimodipine and timolol, as well as with those of other Ca²⁺ channel entry blockers. Important areas for future research in this area are discussed.     

Caveolins and caveolae in ocular physiology and pathophysiology

Caveolae are specialized, invaginated plasma membrane domains that are defined morphologically and by the expression of signature proteins called, caveolins. Caveolae and caveolins are abundant in a variety of cell types including vascular endothelium, glia, and fibroblasts where they play critical roles in transcellular transport, endocytosis, mechanotransduction, cell proliferation, membrane lipid homeostasis, and signal transduction. Given these critical cellular functions, it is surprising that ablation of the caveolae organelle does not result in lethality suggesting instead that caveolae and caveolins play modulatory roles in cellular homeostasis. Caveolar components are also expressed in ocular cell types including retinal vascular cells, Müller glia, retinal pigment epithelium (RPE), conventional aqueous humor outflow cells, the corneal epithelium and endothelium, and the lens epithelium. In the eye, studies of caveolae and other membrane microdomains (i.e., “lipid rafts”) have lagged behind what is a substantial body of literature outside vision science. However, interest in caveolae and their molecular components has increased with accumulating evidence of important roles in vision-related functions such as blood-retinal barrier homeostasis, ocular inflammatory signaling, pathogen entry at the ocular surface, and aqueous humor drainage. The recent association of CAV1/2 gene loci with primary open angle glaucoma and intraocular pressure has further enhanced the need to better understand caveolar functions in the context of ocular physiology and disease. Herein, we provide the first comprehensive review of literature on caveolae, caveolins, and other membrane domains in the context of visual system function. This review highlights the importance of caveolae domains and their components in ocular physiology and pathophysiology and emphasizes the need to better understand these important modulators of cellular function.     

Hydration,fluid regulation and the eye: in health and disease

Variation in systemic hydration status, namely chronic systemic hypohydration or dehydration, can influence the development of several chronic non‐ophthalmic diseases. Owing to the eye's high water content and unique system of fluid regulation, we hypothesized that hydration status may affect the eye in health and disease states. Therefore, we performed a systematic review of the current evidence implicating changes in hydration and their association with ocular physiology and morphological characteristics. We also reviewed relevant clinical correlations of changes in hydration and major common eye diseases. Our findings suggest that systemic hydration status broadly affects a variety of ocular pathophysiologic processes and disease states. For example, dehydration may be associated with development of dry eye syndrome, cataract, refractive changes and retinal vascular disease. On the other hand, excessive hydration is associated with some ocular diseases. Tear fluid osmolarity may be an effective marker of systemic hydration status. Recent studies implicate chronic renin‐angiotensin‐aldosterone system activation in the pathogenesis of diabetic retinopathy and glaucoma but also suggest its antagonism may be a useful therapeutic target. Our findings indicate that assessment of hydration status may be an important consideration in the management of patients with chronic eye diseases and undergoing eye surgery. Further research investigating the role of acute and chronic changes in hydration in individuals with and without ocular disease is warranted.     

Use of erythropoietin in ophthalmology: a review

Erythropoietin (EPO) is a glycoprotein hormone that regulates hematopoiesis in the human body. The presence of EPO and its receptors in different tissues indicates that this hormone has extramedullary effects in other tissues, including the eye. We focus on the biological roles of this hormone in the development and normal physiologic functions of the eye. Furthermore, we explore the role of EPO in the management of different ocular diseases – including diabetic retinopathy, retinopathy of prematurity, inherited retinal degeneration, branch and central retinal vein occlusion, retinal detachment, traumatic optic neuropathy, optic neuritis, methanol optic neuropathy, nonarteritic anterior ischemic optic neuropathy, glaucoma, and scleral necrosis.     

An experimental study of VEGF induced changes in vasoactivity in pig retinal arterioles and the influence of an anti-VEGF agent

ABSTRACT: BACKGROUND: Vascular endothelial growth factor (VEGF) plays an important role in ocular physiology. Anti-VEGF agents are now used for treatment of common retinal diseases. This study characterises the vasoactive properties of VEGF in isolated perfused pig retinal arterioles under normal tone or endothelin-1 (ET-1) pre-contracted conditions and determines the influence of an anti VEGF agent on VEGF induced vasoactivity. METHODS: An isolated perfused retinal arteriole preparation was used. The outer diameter of retinal vessels was monitored at 2 second intervals in response to VEGF and the anti VEGF agent, bevacizumab. The effect of intraluminal delivery of VEGF was determined over a wide concentration range (10-16 to 10-7 M) both with and without pre-contraction with ET-1 (3 x 10-9 M). Bevacizumab (0.35 mg mL-1) was applied extraluminally to determine the influence of bevacizumab on VEGF induced vasoactive changes on ET-1 pre-contracted vessels. RESULTS: In retinal arterioles with normal tone, VEGF induced a concentration dependent contraction at low concentrations, reaching 93.5% at 10-11 M and then contraction was reduced at higher concentrations, recovering to 98.1% at 10-7 M. VEGF produced a potent concentration dependent vasodilatation in arterioles pre-contracted with ET-1. VEGF induced vasodilatation in arterioles pre-contracted with ET-1 was significantly inhibited by bevacizumab. CONCLUSIONS: VEGF induced vasoactive changes in pig retinal arterioles are dependent on concentration and vascular tone. Bevacizumab inhibits VEGF-induced vasodilatation in pre-contracted arterioles.     

丛生蛋白（Clusterin）与眼病的关系

丛生蛋白（clusterin）作为一种多功能分泌糖蛋白,存在于人体的不同组织中,有多种生理功能.Clusterin在眼组织及细胞中的重要作用,表现在可保护视网膜血管内皮细胞和视网膜色素上皮细胞,减少细胞凋亡,而且能增加闭锁小带合成,促进角膜上皮细胞增生和诱导星形胶质细胞、神经元细胞分化,因此一定浓度的clusterin是维持视网膜及角结膜上皮细胞稳定所需要的.鉴于clus-terin在维持血-视网膜屏障和眼表组织结构稳定中的作用,clusterin被认为是糖尿病视网膜病变、年龄相关性黄斑变性等眼底疾病的潜在药物治疗靶点,同时也为治疗假性剥脱性青光眼、Stevens综合征等多种眼前节疾病提供了新思路和新方法.     

Angiotensin-converting enzyme in bovine, feline, and human ocular tissues

Angiotensin-converting enzyme was shown to be present in retinal vessels and neural retina of feline, bovine, and human eyes. It was also demonstrated in the other ocular tissues of feline eyes, in especially high concentration in the highly vascular uveal layer. Its role in the physiology of ocular blood flow and neurophysiology is uncertain, especially in the retina where circulating angiotensin and bradykinin are confined to the intravascular space by the blood-retina barrier, and sufficient data are not available to describe these peptides as transmitters or modulator molecules in the retina.     

Choroidal and retinal thickness in systemic autoimmune and inflammatory diseases: A review

To identify the risk of relapse and subclinical inflammatory stages of systemic autoimmune diseases, new tools are needed. In the recent years, choroidal thickness and retinal thickness measured with ocular coherence tomography (OCT) have been proposed as an inflammatory marker for different systemic diseases, especially for conditions with a vascular component. Our aim in this article is to review the literature regarding the role of choroidal and retinal thickness as a potential inflammatory marker in systemic autoimmune and inflammatory diseases measured by OCT. Current literature suggests that the choroid of patients thickens in active phases of inflammatory diseases with vascular involvement. This pattern is observed in lupus, systemic sclerosis, Behçet disease, spondylitis, and familial Mediterranean fever. Choroidal thickness may decrease with biological treatments, along with systemic inflammation. Repeated flares and long-term disease, however, may thin the choroid, as a result of prolonged insult to the microvasculature and subsequent atrophy. Less is known about the effect of these diseases on retinal thickness. In summary, choroidal and retinal thickness measured by OCT may be promising markers for inflammation in systemic autoimmune and inflammatory diseases; however, more studies are warranted before generalizing choroidal thickness measurements by OCT as a marker for disease activity. The role of retinal thickness is more unclear due to a lack of studies in this field.     

Vascular endothelial growth factors and angiogenesis in eye disease

The vascular endothelial growth factor (VEGF) family of growth factors controls pathological angiogenesis and increased vascular permeability in important eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). The purpose of this review is to develop new insights into the cell biology of VEGFs and vascular cells in angiogenesis and vascular leakage in general, and to provide the rationale and possible pitfalls of inhibition of VEGFs as a therapy for ocular disease. From the literature it is clear that overexpression of VEGFs and their receptors VEGFR-1, VEGFR-2 and VEGFR-3 is causing increased microvascular permeability and angiogenesis in eye conditions such as DR and AMD. When we focus on the VEGF receptors, recent findings suggest a role of VEGFR-1 as a functional receptor for placenta growth factor (PlGF) and vascular endothelial growth factor-A (VEGF)-A in pericytes and vascular smooth muscle cells in vivo rather than in endothelial cells, and strongly suggest involvement of pericytes in early phases of angiogenesis. In addition, the evidence pointing to distinct functions of VEGFs in physiology in and outside the vasculature is reviewed. The cellular distribution of VEGFR-1, VEGFR-2 and VEGFR-3 suggests various specific functions of the VEGF family in normal retina, both in the retinal vasculature and in neuronal elements. Furthermore, we focus on recent findings that VEGFs secreted by epithelia, including the retinal pigment epithelium (RPE), are likely to mediate paracrine vascular survival signals for adjacent endothelia. In the choroid, derailment of this paracrine relation and overexpression of VEGF-A by RPE may explain the pathogenesis of subretinal neovascularisation in AMD. On the other hand, this paracrine relation and other physiological functions of VEGFs may be endangered by therapeutic VEGF inhibition, as is currently used in several clinical trials in DR and AMD.     

The multifunctional human ocular melanocortin system

Immune privilege in the eye involves physical barriers, immune regulation and secreted proteins that together limit the damaging effects of intraocular immune responses and inflammation. The neuropeptide alpha-melanocyte stimulating hormone (α-MSH) normally circulates in the aqueous humour of the anterior chamber and the vitreous fluid, secreted by iris and ciliary epithelium, and retinal pigment epithelium (RPE). α-MSH plays an important role in maintaining ocular immune privilege by helping the development of suppressor immune cells and by activating regulatory T-cells. α-MSH functions by binding to and activating melanocortin receptors (MC1R to MC5R) and receptor accessory proteins (MRAPs) that work in concert with antagonists, otherwise known as the melanocortin system. As well as controlling immune responses and inflammation, a broad range of biological functions is increasingly recognised to be orchestrated by the melanocortin system within ocular tissues. This includes maintaining corneal transparency and immune privilege by limiting corneal (lymph)angiogenesis, sustaining corneal epithelial integrity, protecting corneal endothelium and potentially enhancing corneal graft survival, regulating aqueous tear secretion with implications for dry eye disease, facilitating retinal homeostasis via maintaining blood-retinal barriers, providing neuroprotection in the retina, and controlling abnormal new vessel growth in the choroid and retina. The role of melanocortin signalling in uveal melanocyte melanogenesis however remains unclear compared to its established role in skin melanogenesis. The early application of a melanocortin agonist to downregulate systemic inflammation used adrenocorticotropic hormone (ACTH)-based repository cortisone injection (RCI), but adverse side effects including hypertension, edema, and weight gain, related to increased adrenal gland corticosteroid production, impacted clinical uptake. Compared to ACTH, melanocortin peptides that target MC1R, MC3R, MC4R and/or MC5R, but not adrenal gland MC2R, induce minimal corticosteroid production with fewer adverse systemic effects. Pharmacological advances in synthesising MCR-specific targeted peptides provide further opportunities for treating ocular (and systemic) inflammatory diseases. Following from these observations and a renewed clinical and pharmacological interest in the diverse biological roles of the melanocortin system, this review highlights the physiological and disease-related involvement of this system within human eye tissues. We also review the emerging benefits and versatility of melanocortin receptor targeted peptides as non-steroidal alternatives for inflammatory eye diseases such as non-infectious uveitis and dry eye disease, and translational applications in promoting ocular homeostasis, for example, in corneal transplantation and diabetic retinopathy.     

环状RNA与视网膜发育和视网膜疾病的相关性

Circular RNA (circRNA) is a special type of non-coding RNA molecule ubiquitous in eukaryotes. It has a closed loop structure, and is highly conservative and stable, and has a regulatory role in a variety of diseases. CircRNA can participate in the regulation of retinal inflammation, cell apoptosis, angiogenesis, and oxidative stress response, etc., and plays an important regulatory role in eye development and disease progression. The change of circRNA may be earlier than the change of the fundus morphology, so the circRNA detected in tissues, saliva, blood and exosomes is expected to be used for biomarkers for diagnosis and prognosis of retinal diseases (such as glaucoma, diabetic retinopathy, proliferative vitreoretinopathy, age-related macular degeneration, etc.). Intervention of circRNA expression can significantly affect the biological functions of vascular endothelial cells and regulate vascular permeability. It is expected to be used as a gene therapy method to provide a new direction for the treatment of retinal diseases.(Int Rev Ophthalmol, 2020, 45: 455-458)     

眼细胞的力生物学研究进展

力学因素对于细胞的结构和功能起着重要的调节作用,细胞异常的力学响应可能会导致一系列的病理变化.由于眼压等多种因素的影响,眼部细胞处于不断变化的动态力学环境中,其产生的力学效应在眼内多种组织结构的病理生理过程中发挥重要的作用.本文综述了近年来眼的角膜细胞、巩膜细胞、小梁网细胞、筛板区细胞、视网膜细胞等的力生物学研究进展,从力生物学角度讨论相关疾病可能的发病机制,以提供新的预防和诊疗思路.     

Functions of insulin and insulin receptor signaling in retina: possible implications for diabetic retinopathy

Insulin action regulates the metabolic functions of the classically insulin-responsive tissues: liver, adipose, and skeletal muscle. Evidence also suggests that insulin acts on neural tissue and can modulate neural metabolism, synapse activity, and feeding behaviors. Insulin receptors are expressed on both the vasculature and neurons of the retina, but their functions are not completely defined. Insulin action stimulates neuronal development, differentiation, growth, and survival, rather than stimulating nutrient metabolism, e.g., glucose uptake as in skeletal muscle. Insulin receptors from retinal neurons and blood vessels share many similar properties with insulin receptors from other peripheral tissues, and retinal neurons express numerous proteins that are attributed to the insulin signaling cascade as in other tissues. However, undefined neuron-specific signals downstream of the insulin receptor are likely to also exist. This review compares retinal insulin action to that of peripheral tissues, and demonstrates that the retina is an insulin-sensitive tissue. The review also addresses the hypothesis that dysfunctional insulin receptor signaling in the retina contributes to cell dysfunction and death in retinal diseases.     

Color Doppler Imaging of Retinal Diseases

Color Doppler imaging (CDI) is a widely used method for evaluating ocular circulation that has been used in a number of studies on retinal diseases. CDI assesses blood velocity parameters by using ultrasound waves. In ophthalmology, these assessments are mainly performed on the retrobulbar blood vessels: the ophthalmic, the central retinal, and the short posterior ciliary arteries. In this review, we discuss CDI use for the assessment of retinal diseases classified into the following: vascular diseases, degenerations, dystrophies, and detachment. The retinal vascular diseases that have been investigated by CDI include diabetic retinopathy, retinal vein occlusions, retinal artery occlusions, ocular ischemic conditions, and retinopathy of prematurity. Degenerations and dystrophies included in this review are age-related macular degeneration, myopia, and retinitis pigmentosa. CDI has been used for the differential diagnosis of retinal detachment, as well as the evaluation of retrobulbar circulation in this condition. CDI is valuable for research and is a potentially useful diagnostic tool in the clinical setting.     

Gene expression and the eye

We examined the role of the expression of the various genes in ocular tissues using knockout mice. In this paper, the results are described in three sections: development, physiology, and pathology. Regarding development, the IKK alpha in the development of the ocular surface and maf family genes in the development of the lens were examined. We clearly demonstrated that the deletion of some genes results in disorganization in the development according to the function of the genes. Regarding physiology, c-fos gene was expressed in the subpopulation of retinal neurons under a physiological light/dark cycle, and its expression is dependent on signal transduction system in the retinal cells. Regarding pathology, focal retinal injury of the retina induced the expression of c-fos mRNA in retinal Müller cells. There is a significant contribution of Jun N-terminal phosphorylation to the induction of apoptosis of retinal ganglion cells after optic nerve transection. GLAST is required for normal signal transmission between photoreceptors and bipolar cells and both GLAST and GLT-1 play a neuroprotective role during ischemia in the retina. Blockage of the neurotrophin receptor p 75 rescue photoreceptor apoptosis induced by light exposure whereas the blockage of TrkC increased the photoreceptor cell death.     

APELIN/APJ系统:抗眼内新生血管的新靶点

视网膜新生血管形成是增生性糖尿病视网膜病变、早产儿视网膜病变及缺血性视网膜中央静脉阻塞等视网膜疾病的共同并发症,是这些疾病致盲的主要原因.研究表明多种因子参与新生血管的形成,如血管内皮生长因子、碱性成纤维细胞生长因子等.APELIN是孤儿G蛋白藕连受体(orphan G-protein-coupled receptor,GPCR) APJ的内源性配体,广泛分布于各种组织,具有多种生物学功能.新近研究表明,APELIN在生理及病理性血管新生中具有重要作用,可能成为抗眼内新生血管的新靶点.     

腺苷及其衍生物在眼科应用的研究进展

腺苷是机体内一种重要的生物活性物质，其广泛存在于细胞内液和细胞外液中。在生理状态下，细胞内外的腺苷浓度较低，但在应激情况下，如炎症、缺血、缺氧、创伤、疼痛等，机体内腺苷浓度会大幅度上升，广泛参与多种病理变化过程。腺苷受体具有A1、A2A、A2B、A34种亚型。腺苷通过其受体调控细胞的各种生理功能。目前研究发现腺苷在机体的中枢神经系统、心血管系统、凝血系统等发挥重要作用。近几年来，腺苷在眼部，特别是青光眼、视网膜疾病治疗方面的作用受到广泛关注。腺苷在眼部的作用表现为调节眼压、抑制视网膜新生血管、舒张视网膜血管、调节视网膜神经传导、保护视网膜光感受器和视网膜神经节细胞（RGCs）、抑制炎症反应等。就腺苷和其受体、生物制剂的研究进展及其在眼科的应用前景进行综述。