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The central role of the cardiovascular system is to maintain adequate capillary perfusion. The spatially and temporally heterogeneous nature of capillary perfusion has been reported in some organs. However, such heterogeneous perfusion properties have not been sufficiently explored in the retina. Arguably, spatial and temporal heterogeneity of capillary perfusion could be more predominant in the retina than that in other organs. This is because the retina is one of the highest metabolic demand neural tissues yet it has a limited blood supply due to optical requirements. In addition, the unique heterogeneous distribution of retinal neural cells within different layers and regions, and the significant heterogeneity of intraretinal oxygen distribution and consumption add to the complexity. Retinal blood flow distribution must match consumption of nutrients such as oxygen and glucose within the retina at the cellular level in order to effectively maintain cell survival and function. Sophisticated local blood flow control in the microcirculation is likely required to control the retinal capillary perfusion to supply local retinal tissue and accommodate temporal and spatial variations in metabolic supply and demand. The authors would like to update the knowledge of the retinal microvessel and capillary network and retinal oxidative metabolism from their own studies and the work of others. The coupling between blood supply and energy demands in the retina is particularly interesting. We will mostly describe information regarding the retinal microvessel network and retinal oxidative metabolism relevant to the spatial and temporal heterogeneity of capillary perfusion. We believe that there is significant and necessary spatial and temporal heterogeneity and active regulation of retinal blood flow in the retina, particularly in the macular region. Recently, retinal optical coherence tomography angiography (OCTA) has been widely used in ophthalmology, both experimentally and clinically. OCTA could be a valuable tool for examining retinal microvessel and capillary network structurally and has potential for determining retinal capillary perfusion and its control. We have demonstrated spatial and temporal heterogeneity of capillary perfusion in the retina both experimentally and clinically. We have also found close relationships between the smallest arterioles and capillaries within paired arterioles and venules and determined the distribution of smooth muscle cell contraction proteins in these vessels. Spatial and temporal heterogeneity of retinal capillary perfusion could be a useful parameter to determine retinal microvessel regulatory capability as an early assay for retinal vascular diseases. This topic will be of great interest, not only for the eye but also other organs. The retina could be the best model for such investigations. Unlike cerebral vessels, retinal vessels can be seen even at the capillary level. The purpose of this manuscript is to share our current understanding with the readers and encourage more researchers and clinicians to investigate this field. We begin by reviewing the general principles of microcirculation properties and the spatial and temporal heterogeneity of the capillary perfusion in other organs, before considering the special requirements of the retina. The local heterogeneity of oxygen supply and demand in the retina and the need to have a limited and well-regulated retinal circulation to preserve the transparency of the retina is discussed. We then consider how such a delicate balance of metabolic supply and consumption is achieved. Finally we discuss how new imaging methodologies such as optical coherence tomography angiography may be able to detect the presence of spatial and temporal heterogeneity of capillary perfusion in a clinical setting. We also provide some new information of the control role of very small arterioles in the modulation of retinal capillary perfusion which could be an interesting topic for further investigation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Primary angle-closure glaucoma (PACG) is a common cause of blindness. Angle closure is a fundamental pathologic process in PAGC. With the development of imaging devices for the anterior segment of the eye, a better understanding of the pathogenesis of angle closure has been reached. Aside from pupillary block and plateau iris, multiple-mechanisms are more common contributors for closure of the angle such as choroidal thickness and uveal expansion, which may be responsible for the presenting features of PACG. Recent Genome Wide Association Studies identified several new PACG loci and genes, which may shed light on the molecular mechanisms of PACG. The current classification systems of PACG remain controversial. Focusing the anterior chamber angle is a principal management strategy for PACG. Treatments to open the angle or halt the angle closure process such as laser peripheral iridotomy and/or iridoplasty, as well as cataract extraction, are proving their effectiveness. PACG may be preventable in the early stages if future research can identify which kind of angles and/or persons are more likely to benefit from prophylactic treatment. New treatment strategies like adjusting the psychological status and balancing the sympathetic-parasympathetic nerve activity, and innovative medicines are needed to improve the prognosis of PACG. In this review, we intend to describe current understanding and unknown aspects of PACG, and to share the clinical experience and viewpoints of the authors., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This review is about vascular endothelial phenotype heterogeneity in the retinal and choroidal circulations. It is becoming increasingly clear that the functional and structural heterogeneity is present in the retinal and choroidal circulations. Differential responses of the vessels to vasoactive substances have been shown with intraluminal and extraluminal delivery and in different regions of the same vascular bed. Vascular endothelial phenotype is highly heterogenic and site-specific, particularly in the retinal and choroidal veins. Updated information of such heterogeneity may help us to further understand the control mechanisms of the retinal and choroidal circulations which are important in compensating for the physiological and pathological challenges faced by these vascular beds. The site-specific changes of vascular endothelial phenotype may be linked with endothelium dysfunction, and site-specific diseases such as central and branch retinal vein occlusion. Endothelial dysfunction has been recognized as an initial step for many vascular diseases. Endothelial cells are a strategic and valid target for therapeutic intervention. Fundamentally important questions regarding the role of vascular endothelial cell function in the eye are discussed., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Retinal ganglion cells (RGCs) are specialized projection neurons that relay an immense amount of visual information from the retina to the brain. RGC signal inputs are collected by dendrites and output is distributed from the cell body via very thin (0.5-1 μm) and long (∼50 mm) axons. The RGC cell body is larger than other retinal neurons, but is still only a very small fraction (one ten thousandths) of the length and total surface area of the axon. The total distance traversed by RGCs extends from the retina, starting from synapses with bipolar and amacrine cells, to the brain, to synapses with neurons in the lateral geniculate nucleus. This review will focus on the energy demands of RGCs and the relevant tissues that surround them. RGC survival and function unexceptionally depends upon free energy, predominantly adenosine triphosphate (ATP). RGC energy metabolism is vastly different when compared to that of the photoreceptors. Each subcellular component of the RGC is remarkably different in terms of structure, function and extracellular environment. The energy demands and distribution of each component are also distinct as evidenced by the uneven distribution of mitochondria and ATP within the RGC - signifying the presence of intracellular energy gradients. In this review we will describe RGCs as having four subcellular components, (1) Dendrites, (2) Cell body, (3) Non-myelinated axon, including intraocular and optic nerve head portions, and (4) Myelinated axon, including the intra-orbital and intracranial portions. We will also describe how RGCs integrate information from each subcellular component in order achieve intracellular homeostatic stability as well as respond to perturbations in the extracellular environment. The possible cellular mechanisms such as axonal transport and axonal cytoskeleton proteins that are involved in maintaining RGC energy homeostasis during normal and disease conditions will also be discussed in depth. The emphasis of this review will be on energetic mechanisms within RGC components that have the most relevance to clinical ophthalmology., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

This review considers the critical role of the conjunctiva in determining the success or failure of glaucoma filtration surgery. Glaucoma filtration surgery can be defined as an attempt to lower intraocular pressure (IOP) by the surgical formation of an artificial drainage pathway from the anterior chamber to the subconjunctival space. Many types of glaucoma filtration surgery have been developed since the first attempts almost 180 years ago. The wide range of new techniques and devices currently under investigation is testament to the limitations of current techniques and the need for improved therapeutic outcomes. Whilst great attention has been paid to surgical techniques and devices to create the drainage pathway, relatively little attention has been given to address the question of why drainage from such artificial pathways is often problematic. This is in contrast to normal drainage pathways which last a lifetime. Furthermore, the consequences of potential changes in aqueous humour properties induced by glaucoma filtration surgery have not been sufficiently addressed. The mechanisms by which aqueous fluid is drained from the subconjunctival space after filtration surgery have also received relatively little attention. We propose that factors such as the degree of tissue damage during surgery, the surrounding tissue reaction to any surgical implant, and the degree of disruption of normal aqueous properties, are all factors which influence the successful formation of long term drainage channels from the conjunctiva, and that these channels are the key to successful filtration surgery. In recent years it has been suggested that the rate of fluid drainage from the subconjunctival space is actually the determining factor in the resultant IOP reduction. Improved knowledge of aqueous humour induced changes in such drainage pathways has the potential to significantly improve the surgical management of glaucoma. We describe for the first time a novel type of drainage surgery which attempts to minimise surgical trauma to the overlying conjunctiva. The rationale is that a healthy conjunctiva allows drainage channels to form and less opportunity for inflammation and scar tissue formation which are a frequent cause of failure in glaucoma filtration surgery. Successful drainage over extended periods of time has been demonstrated in monkey and rabbit eyes. Long lasting drainage pathways were clearly associated with the presence of lymphatic drainage pathways. A new philosophy in glaucoma drainage surgery is proposed in which minimisation of surgical trauma to the conjunctiva and the encouragement of the development of conjunctival drainage pathways, particularly lymphatic pathways, are central pillars to a successful outcome in glaucoma filtration surgery.

The purpose of this review is to outline the techniques and applications for isolated ocular vascular preparations and their significance to ophthalmic research. Various isolated ocular vascular preparations have been utilized in studies of ocular vascular biology, physiology and pharmacology, including work in both normal and diseased conditions. However, there is still significant potential for further studies to improve our understanding of the ocular circulation and its regulation. Experience has shown that there is no single preparation capable of addressing all of the questions that must be answered if a complete understanding of mechanisms of vascular regulation in the eye is to be achieved. Rather, it is necessary to select the appropriate preparation and techniques to address each individual question in the most appropriate manner. In this review, particular emphasis is placed on the applications for isolated ocular preparations and the relevance of such studies to our understanding of the pathogenesis of eye diseases involving the vasculature. Examples are given where therapeutic approaches in diabetes and glaucoma are assessed in terms of their impact on the vasoactive properties of the ocular vasculature.A significant heterogeneity is present in the different parts of the ocular vasculature, not only in the structural and functional properties of vessel itself, but also in terms of the tissue environment and innervation. A single vasoactive agent may also have different effects when applied to the inside or the outside of the same region of a vessel. The vasoactive response of the vascular system as a whole is what determines the rate of blood flow through the system, but this is regulated by a multitude of factors in different regions of the vascular network. Isolating individual components of the ocular vasculature is readily achievable for the extraocular vessels such as the ophthalmic or ophthalmocilliary arteries, which can be studied in myograph type systems measuring the mechanical vasoactive force generated by the vessel. Retinal vessels from very large animals can also be studied in this way, but the small diameter of the retinal vessels in most species requires a perfusion rather than myograph based technique. Perfusion based studies of vessel diameter in response to vasoactive stimuli can be applied to individual retinal arteries and their branches. Perfusion of more complex elements of the ocular vasculature such as isolated segments of the retina or ciliary body, or whole isolated perfused eyes may use the perfusate pressure as the determinant of vasoactive state. However, when several components of the ocular vasculature are being perfused simultaneously it may be difficult to separate out the contribution from the different vascular elements. The advantage of isolated preparations is that systemic influences can be eliminated, and vascular components can be studied that are inaccessible in vivo. The disadvantage is that no matter how well controlled the in vitro environment may be, it will always be a relatively poor mimic of the in vivo conditions. However, such in vitro work has certainly improved our understanding of the vasoactive properties of different regions of the ocular vasculature in both health and disease.

Maintenance of an adequate oxygen supply to the retina is critical for retinal function. In species with vascularised retinas, such as man, oxygen is delivered to the retina via a combination of the choroidal vascular bed, which lies immediately behind the retina, and the retinal vasculature, which lies within the inner retina. The high-oxygen demands of the retina, and the relatively sparse nature of the retinal vasculature, are thought to contribute to the particular vulnerability of the retina to vascular disease. A large proportion of retinal blindness is associated with diseases having a vascular component, and disrupted oxygen supply to the retina is likely to be a critical factor. Much attention has therefore been directed at determining the intraretinal oxygen environment in healthy and diseased eyes. Measurements of oxygen levels within the retina have largely been restricted to animal studies in which oxygen sensitive microelectrodes can be used to obtain high-resolution measurements of oxygen tension as a function of retinal depth. Such measurements can immediately identify which retinal layers are supplied with oxygen from the different vascular elements. Additionally, in the outer retinal layers, which do not have any intrinsic oxygen sources, the oxygen distribution can be analysed mathematically to quantify the oxygen consumption rate of specific retinal layers. This has revealed a remarkable heterogeneity of oxygen requirements of different components of the outer retina, with the inner segments of the photoreceptors being the dominant oxygen consumers. Since the presence of the retinal vasculature precludes such a simple quantitative analysis of local oxygen consumption within the inner retina, our understanding of the oxygen needs of the inner retinal components is much less complete. Although several lines of evidence suggest that in the more commonly studied species such as cat, pig, and rat, the oxygen demands of the inner retina as a whole is broadly comparable to that of the outer retina, exactly which cell layers within the inner retina have the most stringent oxygen demands is not known. This may be a critical issue if the cell types most at risk from disrupted oxygen supply are to be identified. This paper reviews our current understanding of the oxygen requirements of the inner and outer retina and presents new data and mathematical models which identify three dominant oxygen-consuming layers in the rat retina. These are the inner segments of the photoreceptors, the outer plexiform layer, and the deeper region of the inner plexiform layer. We also address the intriguing question of how the oxygen requirements of the inner retina are met in those species which naturally have a poorly vascularised, or even totally avascular retina. We present measurements of the intraretinal oxygen distribution in two species of laboratory animal possessing such retinas, the rabbit and the guinea pig. The rabbit has a predominantly avascular retina, with only a narrow band of retinal vasculature, and the guinea pig retina is completely avascular. Both these animals demonstrate species adaptations in which the oxygen requirement of their inner retinas are extremely low when compared to that of their outer retinas. This finding both uncovers a remarkable ability of the inner retina in avascular species to function in a low-oxygen environment, and also highlights the dangers of extrapolating findings from avascular retinas to infer metabolic requirements of vascularised retinas. Different species also demonstrate a marked diversity in the manner in which intraretinal oxygen distribution is influenced by increases in systemic oxygen level. In the vascularised rat retina, the inner retinal oxygen increase is muted by a combination of increased oxygen consumption and a reduction of net oxygen delivery from the retinal circulation. The avascular retina of the guinea pig demonstrated a novel and powerful regulatory mechanism that prevents any dramatic rise in choroidal oxygen levels and keeps retinal oxygen levels within the normal physiological range. In contrast, in the avascular regions of the rabbit retina the choroidal oxygen level passively follows the increase in systemic oxygenation, and there is a dramatic rise in oxygen level in all retinal layers. The presence or absence of oxygen-regulating mechanisms may well reflect important survival strategies for the retina which are not yet understood. Intraretinal oxygen measurements in rat models of retinal disease are also presented. We describe how oxygen distribution across the rat retina is influenced by manipulation of systemic blood pressure. We examine the effect of acute and chronic occlusion of the retinal vasculature, and explore the feasibility of meeting the oxygen needs of the ischemic retina from the choroid. (ABSTRACT TRUNCATED)