New insights into the retinal circulation: Inflammatory lipid mediators in ischemic retinopathy

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Prostaglandins, Leukotrienes and Essential Fatty Acids 72 (2005) 301–325 www.elsevier.com/locate/plefa

Review

New insights into the retinal circulation: Inflammatory lipid mediators in ischemic retinopathy Pierre Hardya,, Martin Beauchampa, Florian Sennlauba, Fernand Gobeil Jr.b, Lise Tremblaya, Bupe Mwaikamboc, Pierre Lachapellec, Sylvain Chemtoba,c a Departments of Obstetrics, Ophthalmology, Pediatrics, and Pharmacology, Research Center Sainte-Justine Hospital and University of Montreal, Montreal, Quebec, Canada, H3T 1C5 b Department of Pharmacology, Sherbrooke University, Sherbrooke, Quebec, Canada c Departments of Pharmacology & Therapeutics and Ophthalmology, McGill University, Montreal, Quebec, Canada

Received 21 December 2004; accepted 11 February 2005

Abstract Ischemic proliferative retinopathy develops in various retinal disorders, including retinal vein occlusion, diabetic retinopathy and retinopathy of prematurity. Ischemic retinopathy remains a common cause of visual impairment and blindness in the industrialized world due to relatively ineffective treatment. Oxygen-induced retinopathy (OIR) is an established model of retinopathy of prematurity associated with vascular cell injury culminating in microvascular degeneration, which precedes an abnormal neovascularization. The retina is a tissue particularly rich in polyunsaturated fatty acids and the ischemic retina becomes highly sensitive to lipid peroxidation initiated by oxygenated free radicals. Consequently, the retina constitutes an excellent model for testing the functional consequences of membrane lipid peroxidation. Retinal tissue responds to physiological and pathophysiological stimuli by the activation of phospholipases and the consequent release from membrane phospholipids of biologically active metabolites. Activation of phospholipase A2 is the first step in the synthesis of two important classes of lipid second messengers, the eicosanoids and a membrane-derived phospholipid mediator platelet-activating factor (PAF). These lipid mediators accumulate in the retina in response to injury and a physiologic role of these metabolites in retinal vasculature remains for the most part to be determined; albeit proposed roles have been suggested for some. The eicosanoids, in particular the prostanoids, thromboxane (TXA2) and PAF are abundantly generated following an oxidant stress and contribute to neurovascular injury. TXA2 and PAF play an important role in the retinal microvacular degeneration of OIR by directly inducing endothelial cell death and potentially could contribute to the pathogenesis of ischemic retinopathies. Despite these advances there are still a number of important questions that remain to be answered before we can confidently target pathological signals. This review focuses on mechanisms that precede the development of neovascularization, most notably regarding the role of lipid mediators that partake in microvascular degeneration. r 2005 Elsevier Ltd. All rights reserved.

Abbreviations: cAMP, adenosine 30 ; 50 -cyclic monophosphate; AA, arachidonic acid; COX, cyclooxygenase; ChBF, choroidal blood flow; DHA, docosahexaenoic acid; GPCR, G protein-coupled receptor; IP3, inositol 1, 4, 5-triphosphate; NOS, nitric oxide synthase; iNOS, inducible nitric oxide synthase; eNOS, endothelial nitric oxide synthase; OIR, oxygen-induced ischemic retinopathy; PAF, platelet-activating factor; PG, prostaglandin; PGH2, prostaglandin synthase; PLA2, phospholipase A2; PTX, pertussis toxin; PUFA, polyunsaturated fatty acids; RBF, retinal blood flow; ROS, reactive oxygen species; ROP, retinopathy of prematurity; TP, thromboxane A2 receptor; TXA2, thromboxane A2; TXS, thromboxane synthase; VEGF, vascular endothelial growth factor Corresponding author. Tel.: +1 514 345 4931  4729; fax: +1 514 345 4801. E-mail address: [email protected] (P. Hardy). 0952-3278/$ - see front matter r 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.plefa.2005.02.004

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1. Introduction The retina is an integral part of the central nervous system communicating directly with the brain via ganglion cell axons passing through the optic nerve. The retina shares many functional and structural characteristics with the brain. One striking difference between the retina and brain however, is the relative resistance of the retina to an ischemic insult, which may reflect its peculiar metabolism and unique environment [1]. Mammalian retinal ischemia results in irreversible morphological and functional changes. Ischemic retinopathy develops when the retinal blood flow is insufficient to match the metabolic needs of the retina, the highest demands of any tissue. At the cellular level, ischemic retinal injury consists of a self-reinforcing destructive cascade involving neuronal depolarisation, calcium influx, and oxidative stress initiated by energy failure and increased glutamatergic stimulation [2]. Retinal phospholipids, fatty acid products including eicosanoids and related products have important roles in ocular physiology and pathophysiology. Lipid mediators generated in the retina by oxidative pathways play essential roles in vascular homeostasis and disease by activating signal transduction pathways that control a variety of cellular functions, including visual functions, vascular tone, and gene expression [3,4]. Several enzyme families generate oxidized lipids, and a number of these are either constitutively expressed or inducible in the endothelium. These enzymes may also generate low levels of lipid-derived radicals in the vasculature following escape of substrate radicals from the active site [5]. Lipid oxidation enzymes are often up-regulated in ischemic retinopathies, with several lines of evidence suggesting that they play a central role in the pathogenesis of the disease process itself [6]. A number of animal models and analytical techniques have been used to study retinal ischemia, and an increasing number of treatments have been shown to interrupt the ‘‘ischemic cascade’’ and attenuate the detrimental effects of retinal ischemia [2]. Thus far, however, success in the laboratory has not been translated to the clinical setting. Difficulties regarding the route of administration, dosage, and adverse effects may render certain experimental treatments clinically unusable. Furthermore, neuroprotection-based treatment strategies have so far been disappointing. Given the increasing understanding of the events involved in ischemic neuronal injury it is hoped that clinically effective treatments for retinal ischemia will soon be available. Extensive reviews on retinal angiogenesis have been documented [7–9]. This review will focus on a crucial preceding predisposing event, namely microvascular obliteration. The first section of this paper will describe the retinal circulation and how it is regulated. This will

be followed by a discussion on retinovascular susceptibility to oxygen and current experimental models. Finally, we will review some new insights into the role of oxidative stress-induced lipid mediators in mechanisms of retinal microvascular dysfunction and potential therapeutic strategies.

2. Retinal circulation and its ontogenic regulation 2.1. Retinal circulation Retinal circulation is responsible for the delivery of oxygen and nutrients to different structures of the retina without interfering with visual functions. To achieve this complex task in mammals, humans, and other primates, two separate vascular systems partake in the process, i.e. the retinal vascularization and the uveal or choroidal vascularization [1]. Branches of the central retinal artery which arise directly from the ophthalmic artery are responsible for the retinal vascularization. It supplies the inner twothirds of the retina through three layers of capillary networks including the radial peripapillary capillaries (RPCs), and a superficial and deep layer of capillaries [10]. The latter supply two-thirds of the inner retina, while the outer third is supplied by the high flow choroid circulation. By passing centrifugally from the optic disc to the periphery, the retinal circulation shows progressive slowing of linear flow rate in arterioles and capillaries. Therefore, retinal circulation is characterized by a low blood flow and a high level of oxygen extraction; arteriovenous difference in pO2 is about 40% [11]. To ensure a selective exchange of substances between the blood and surrounding tissues, retinal vascular endothelial cells are nonfenestrated, tightly joined, and form an inner blood-retinal barrier between the retinal capillaries and the retinal tissue. The second source of blood supply to the retina are the choroidal blood vessels. Choroidal arteries arise from posterior ciliary arteries and branches of Sinn’s circle, located around the optic disc, which break up into fan-shaped lobules of capillaries that supply the choroids [12]. This network of capillaries, named choriocapillaris, plays a crucial role by providing nutrients and oxygen to the retinal pigment epithelium (RPE) and to the photoreceptors in the outer part of retina, which exhibit high oxygen consumption. Retinal blood vessel development begins during the fourth month of gestation in the human fetus and is only completed after 40 weeks (at term) [13]. In the rodent, the retinal vasculature develops postnatally and extends to fill the peripheral avascular retina which occurs by a combination of vasculogenesis and angiogenesis [14,15]. During the development of the retinal vasculature, vessel growth is guided by glial cells that secrete

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hypoxia-induced vascular endothelial growth factor (VEGF) [16,17]. Superficial retinal vessels form by vasculogenesis starting at the optic nerve and developing along a gradient from posterior to anterior retina. Vessels sprout from superficial retinal vessels and invade into the retina to form the intermediate and deep capillary beds by angiogenesis. Once vascular beds are formed, they are remodeled based on oxygen tension within the tissue [18]. Remodeling of vessels is likely to be a form of angiogenesis and certainly involves hypoxia-regulated genes [19]. Therefore, in infants born prematurely, retinal vascularization is incomplete and constitutes a peripheral avascular zone that varies with gestational age whereas the choriocapillaris, which is already established, supplies the developing outer neural retina [20–24]. 2.2. Regulatory determinants of retinal and choroidal circulations in the adult and the newborn The presence of mechanisms that regulate retinal circulation may well reflect important survival strategies for the retina which are not yet understood. As in most tissues, the regulation of the circulation is complex. Many different local and systemic factors can exert an influence. Local physical (e.g. variations in perfusion pressure) and metabolic factors (e.g. variations in pO2, pCO2 and pH) attempt to adapt flow to local needs, while systemic factors (circulating hormones and the autonomic nervous system) regulate the distribution of the cardiac output over different vascular beds. Although the eye has a rich autonomic innervation, nerve endings only extend to the uvea and the extraocular part of the retinal blood vessels, while intraocular segments of the retinal blood vessels are not adrenergically, cholinergically, or peptidergically innervated [25–28]. Since the retinal tissue lacks vascular innervation retinal arterial tone is largely regulated by local factors. 2.2.1. Autoregulatory responses of RBF and ChBF to changes in perfusion pressure The flow through a vascular bed is determined by both perfusion pressure and vascular resistance. The mechanism which provides the ability of the retinal vessels to keep blood flow constant despite changes in perfusion pressure or, the ability of a tissue to adapt blood flow to metabolic needs, is termed autoregulation [29]. In the adult, retinal blood flow (RBF) is maintained constant over a wide range of perfusion pressure from 45 to 145 mm Hg whereas RBF is autoregulated over only 45 to 85 mm Hg in the newborn (Fig. 1A) [20,21,30–35]. Choroidal blood flow (ChBF) is also autoregulated in the adult over a wide range of perfusion pressure but there is almost complete absence

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of autoregulation of ChBF in the newborn (Fig. 1A) [21,30,31,36–42]. Consequently, during an acute rise in perfusion pressure, RBF and ChBF of the newborn cannot be maintained constant, resulting in potentially toxic increased delivery of oxygen to the retina [21,31,43–47]. 2.2.2. RBF and ChBF autoregulatory response to oxygen tension Ocular blood flow autoregulation also operates in response to changes in blood oxygen tension. Observations suggest that variations in oxygen tension are mainly compensated by RBF autoregulatory mechanisms. Thus, several studies have shown that hypoxemia causes an increase in RBF [48,49]. In response to hyperoxia, the retinal vasculature constricts comparably in the adult and the newborn (Fig. 1B) [21,37,38,41,44,50–53]. On the other hand, compared to the adult, choroidal vessels of the newborn do not constrict in response to hyperoxia, thus causing increased delivery of potentially toxic levels of oxygen to the newborn retina [21,31,41,54–56]. Since immature retinal tissues lack developed antioxidant systems, hyperoxygenation favors peroxidation which in turn leads to microvascular injury and consequently ischemia. This physiological cascade of events ultimately predisposes the newborn to the development of a vasoproliferative retinopathy, commonly termed retinopathy of prematurity (ROP) [21,31,41]. 2.2.3. RBF and ChBF regulation by carbon dioxide Changes in carbon dioxide tension play a significant role in the regulation of RBF and ChBF, such that one can observe a 300–400% rise in blood flow in response to a two-fold increase in CO2 tension from normal values [57]. A rapid rise in ocular circulation induced by acute hypercapnia has been shown to be prostaglandindependent. During sustained hypercapnia this increase in prostaglandin, mostly PGE2, induces endothelial NO synthase expression, which releases NO and in turn mediates the delayed hypercapnia-induced rise in ocular hemodynamics [58]. This marked hypercapnia-induced ocular hyperemia is clinically relevant since hypercapnia is associated with ROP in humans and experimental animals [59]. Thus, both the acute and sustained phases of hypercapnia are somewhat prostaglandin-dependent. Hypocapnia on the other hand leads to a modest decrease in RBF and ChBF. 2.2.4. Response to autoregulatory stimuli: retinal and systemic endothelial factors During the last decade our understanding of the blood flow regulation in healthy and/or diseased eyes has been improved by research targeting the role of the vascular endothelium in RBF autoregulation [4,60–62]. It is now well established that vascular endothelial cells

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Fig. 1. Deficiency of autoregulation in the developing subject. (A) Deficiency in retinal and choroidal blood flow autoregulation in response to a change in ocular perfusion pressure (OPP) in the newborn. Inhibition of cyclooxygenase (COX) improves ocular blood flow autoregulation. (B) Deficiency in choroidal blood flow autoregulation in response to a rise in O2 tension in the newborn relative to the adult. This is partly due to insufficient constrictors but mostly to increased formation of vasorelaxants in neonates.

produce different vasodilating and vasoconstricting factors under basal conditions and in response to varying physiologic stresses such as changes in blood pressure, vessel wall stress, and metabolic changes as elevation of oxygen (hyperoxia) [63]. These endothelial factors may originate from both vascular and/or perivascular retinal tissues and may include messenger molecules such as nitric oxide, adenosine, endothelin, and a number of bioactive lipid mediators including prostaglandins and other eicosanoids, platelet-activating factor (PAF) and isoprostanes [4,21,63–72]. The perinatal period is associated with abundant generation of prostaglandins, and these have been found

to impact upon vasomotor tone. The major consequences of this excess amount of prostaglandins in the newborn seems to be created by the production of a dominant mediator, notably NO; this effect is dependent upon PGD2 and PGE2 which in turn governs the perinatal expression of endothelial NO synthase in the neural vasculature [73,74]. Moreover, NO exerts part of its vasomotor effects via PGI2 in the eye [75]. Accordingly, the immature subject forms excess NO which hinders the normal autoregulatory response of the choroid and leads to excess delivery of O2 to the retinal tissue; this effect relies upon an intimate interplay between NO and prostaglandins [30,41].

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3. Retinovascular susceptibility to oxygen and an experimental models 3.1. Oxygen-induced ischemic retinopathy: an experimental model for retinopathy of prematurity 3.1.1. Retinopathy of prematurity As indicated above the immature retina poorly regulates oxygen delivery to its tissue, leading to excess oxygenation. This excessive retinal oxygenation plays a significant role in the pathogenesis of ROP, a major cause of blindness in children [76,77]. Both the absolute oxygen tension of gas used and the duration of its administration are believed to be important components in the genesis of the retinopathy. ROP develops in two distinct phases [78]. First, when the retina is exposed to high concentrations of oxygen, normal vascular development ceases and large areas of the newly formed immature retinal vessels obliterate, which altogether compromise perfusion and leads to ischemia [50]. This vasoobliterative ischemic phase is paramount in predisposing to the subsequent neovascularization. The second phase is characterized by an attempt of the tissue to compensate for the resulting ischemia, leading to an exaggerated intravitreal preretinal neovascularization. The latter event may ultimately lead to retinal detachment and vision loss. Of the various factors implicated in this ischemic-hypoxia-induced neovascular phase VEGF-A plays a dominant role [79–81]. 3.1.2. Oxygen-induced retinopathy Oxygen-induced retinopathy (OIR) is an in vivo model of ROP and reproduces many features of the human condition [14,80,82–92]. In this model, young pups are exposed to hyperoxia during which retinal vascular development is hindered and vasoobliteration takes place; upon replacing pups to normoxia, the inner retina relatively devoid of vasculature triggers an angiogenic response which leads to excessive abnormal preretinal neovascularization, as seen in ROP and diabetic retinopathy. This model has been tested in a number of species, and the extent of neovascularization is further aggravated by frequently oscillating O2 tensions between hypoxic and mildly hyperoxic ranges; OIR is most commonly reproduced in the rat and mouse [6,82,93–96]. As observed in ROP, OIR culminates in arrest in vascular development and microvascular degeneration, which precedes abnormal neovascularization [14,82,88,95,97–99]. The process begins in isolated retinal capillaries that become acellular and nonperfused, a process called vasoobliteration or vasoattenuation. It further extends to groups of capillaries, and then advances centripetally to involve the arterioles and their side branches [100]. Vessel regression in ischemic retinopathies represents an exaggeration of an otherwise natural response to oxygen surplus. Normally, the tissue

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responds to excess oxygen by trimming its microvasculature to the extent that oxygen supply is reset to match the metabolic requirements of the tissue. It is noteworthy that the choroidal vasculature, which is completely formed at birth, is unaffected by the hyperoxic insult. In essence, OIR is an oxidative insult to a developing vasculature which leads to cessation in normal vascular development, microvascular degeneration, ischemia, and sight-threatening exaggerated angiogenesis [99,101–103]. Although abundant studies have explored the factors responsible for neovascularization, the mechanisms of the cardinal preceding microvascular degeneration are only now in the process of being uncovered. 3.2. Susceptibility of the perivascular and vascular retinal tissues to oxidative stress 3.2.1. Reactive oxygen species in retinal tissue There are many types of radicals, but those of greatest concern to biological systems are derived from oxygen, and known collectively as reactive oxygen species (ROS). Oxygen-derived radicals are generated constantly as part of normal aerobic life. They are formed, among other sources, in the mitochondria, as oxygen is reduced along the electron transport chain. When generated in excess under oxidative stress conditions, oxygen-derived radicals can disrupt a broad range of important cellular components containing lipids, proteins and nucleic acids; consequently cytotoxicity can occur. Of relevance, the retina is a tissue rich in mitochondria which is able to maintain a very high rate of oxidative metabolism, even under normal oxygen conditions [104]. To maintain the high oxygen consumption, an abundant oxygen supply is mainly ensured by the choroidal circulation which is characterized by a high blood flow. Therefore, the specific organization of the ocular circulation could contribute to enhance the susceptibility of the retinal tissue to oxidative stress under hyperoxic conditions in the immature subject. In addition, the retina contains a large amount of molecular photosensitizers, which upon photic excitation generate free radicals [44,105–107]. Furthermore, in newborns, in contrast to the adult, there is more free iron in neural tissue to readily catalyze oxidizing reactions [108,109]. In addition to the mitochondrial respiratory chain, ROS are also formed as necessary intermediates in a variety of normal biochemical reactions. In fact, a variety of enzymes and transporters contribute to the generation of free radicals. These include the endothelial cell xanthine oxidase, NADPH oxidase, cyclooxygenase (COX), nitric oxide synthase (NOS) and to a lesser extent the lipoxygenase pathways. Interestingly, COX and NOS activities are high in the neonatal period and have been shown to contribute in concert to

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peroxidation in ocular tissues. Likewise, there exists a positive feedback interaction between free radicals and COX activity in ocular tissues, such that during oxidative stress, the COX pathway is an important producer of free radicals and in turn is also activated by them [110]. 3.2.2. Effects of reactive oxygen species on retinal blood vessels ROS play an important role in the retinal vasoobliteration associated with OIR [101,102,111]. Oxidant stress can induce retinovascular injury by reducing tissue perfusion caused by significant vasoconstriction and/or by affecting platelet aggregation, as well as through direct cytotoxic effects [112–116]. In addition, oxygenderived radicals and their metabolites affect retinal vasomotor tone and those changes depend on the types of blood vessels, the types and concentrations of free radical, and the developmental stage. For example, peroxides cause at lower concentrations a small vasodilatation but as their concentration rises, this vasodilatation readily switches to a marked TXA2-dependent constriction [43,110,117]. Of interest, such peroxideinduced vasodilatation has been invoked during RBF and ChBF autoregulatory adjustments, mediated via a prostaglandin-dependent mechanism [31]. In addition, peroxide-induced constriction is more pronounced and sustained in the immature subject compared to that observed in adult subjects due to increased and unopposed (by PGI2) TXA2 generation [43,117]. This shift in ratio of PGI2 towards TXA2 has previously been explained by an endoperoxide steal whereby PGH2 generated by endothelium is used by platelet thromboxane synthase to generate TXA2 in the presence of lipid peroxides [118,119]. Thus peroxidation not only impacts on tissue integrity but also significantly governs ocular hemodynamics in the developing subject [110]. 3.2.3. Lipid peroxidation substrates in retinal tissue Among the most established toxic effects of ROS is damage to cellular membranes, which is initiated by a process known as lipid peroxidation. A common target for peroxidation is polyunsaturated fatty acids (PUFAs) present in membrane phospholipids. Lipid peroxidation of retinal membrane PUFAs results in loss of membrane function and structural integrity [120,121]. For reasons that remain unclear, retinal endothelial cells seem particularly susceptible to peroxidation-induced injury, whereas pericytes, smooth muscle cells, and perivascular astrocytes are relatively resistant [122–125]. The retina is highly susceptible to lipid peroxidation since 20% of its dry weight is composed of lipids containing a high level of different PUFAs including docosahexaenoic acid (DHA; 22:6o-3), arachidonic acid (AA; 20:4o-6) and choline phosphoglyceride. The entire retina contains very high levels of DHA [126,127]. DHA

is crucial in the visual process and therefore, accounts for about 25–50% of the total esterified fatty acids that are mainly concentrated in the rod photoreceptor outer segments [128]. Furthermore, lower levels of DHA have been reported in the human macular region (central part of the retina and most important for visual functions) compared with the peripheral retina. This suggests that the greater oxidant challenge of the macula consumes DHA [129]. AA represents about 5–15% of total esterified fatty acids in phospholipids, and is a precursor for vasoactive prostaglandins, whereas choline phosphoglycerides comprise almost half of vertebrate retinal phospholipids [130,131]. This very high proportion of long-chain PUFAs found in all phospholipid classes is a feature unique to retinal lipids. Retinal vessels, in contrast to parenchyma, contain saturated fatty acids like stearic acid as well as unsaturated ones including AA and DHA which exist in equal amounts [45,127,132]. But the important DHA precursor, eicosapentaenoic acid (20:5o-3), is not detected in retinal vessels. 3.2.4. Antioxidant systems in the newborn retina Antioxidants are molecules which can safely interact with ROS and terminate the chain reaction before vital molecules are damaged. The concentration of all the major components of the antioxidant systems in neonates, which include heme oxygenase-1, metallothionein, Cu–Zn superoxide dismutase, catalase, vitamins C and E, and glutathione peroxidase, have been shown to be reduced in retinal tissues [133–136]. Therefore, premature infants, exhibiting underdeveloped antioxidant defenses, are particularly sensitive to the toxic effects incurred by relative excesses in oxygen [5,137]. Altogether, a limited ability of the newborn to autoregulate, the abundant unsaturated fatty acids in retina, and the reduced antioxidant systems, renders the ocular vasculature of the newborn more vulnerable to oxidative damage.

4. Effects of lipid mediators in retinal microvascular dysfunction 4.1. Retinovascular injury, leukocyte invasion and generation of lipid mediators Ischemic-reperfusion injuries as seen in proliferative retinopathies such as ROP are associated with retinal vascular leakage, capillary nonperfusion, and endothelial cell damage, which are temporary and spatially associated with retinal leukocyte stasis [138–141]. A rate-determining role for leukocyte-endothelial cell adhesion in the initiation and propagation of reperfusion injury is supported by reports describing retinal microvascular dysfunction and tissue injury following

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ischemia and reperfusion in animals receiving neutralizing antibodies directed against certain leukocyte adhesion receptors, and in mutant mice that are genetically deficient in these adhesion receptors [138,140,141]. Of relevance, the high activity of NADPH oxidase of neutrophils partakes in generation of ROS. These in turn activate retinal cells to augment the oxidative process and ultimately resulting in cell death. 4.1.1. Phospholipase A2: biological properties, expression and regulation in the retina Phospholipase A2 (PLA2) belongs to a family of enzymes that catalyzes the hydrolysis of sn-2 fatty acids from membrane phospholipids. PLA2s are involved in a complex network of signaling pathways that link receptor agonists, oxidative agents, and proinflammatory cytokines to the release of several biologically active phospholipid metabolites such as AA, eicosanoids, PAF, and lysophospholipids. PLA2s acting on membrane phospholipids have been implicated in intracellular membrane trafficking, differentiation, proliferation, and apoptotic processes [142]. There is a wealth of evidence that the major enzyme PLA2 is activated by oxidative stresses [143–146]. PLA2 is activated by ischemia/reperfusion in the retina and via the released mediators contributes to free radical formation [5,130,147–150]. Based on their biological properties, there are more than 19 different isoforms of PLA2 in mammalian systems, and they can be classified into 4 main types: the secretory enzymes (sPLA2), the cytosolic PLA2 (cPLA2), the Ca2+-independent (iPLA2), and the selective acetyl hydrolases of PAF. These groups of PLA2 enzymes differ from each other in terms of substrate specificity, in their overall structure, Ca2+ requirements, pH optima, lipid modification and susceptibility to pharmacologic inhibition. The secretory (s) PLA2s are low molecular weight and comprise 10 groups: IB, IIA, IIC, IID, IIE, IIF, III, V, X, and XIIA [151]. Upon activation, sPLA2 bind to receptors, and may act as intercellular signaling modulators. sPLA2 enzymes exhibit no preference for AA in the sn-2 position of phospholipids. Two structural features are of functional interest: the catalytic site and the interfacial binding site that interact with multiple phospholipids at target membranes; sPLA2 must first anchor to the membrane in order to gain access to its substrate. The catalytic site is very well conserved between sPLA2 enzymes, and calcium is an essential catalytic cofactor [152,153]. Cytosolic PLA2 (cPLA2) or group IV, is of high molecular mass (85 kDa), and is ubiquitously expressed in the cytosolic fraction of nearly all cell types studied. This enzyme preferentially hydrolyzes phospholipids at the sn-2 position of glycerophospholipids containing AA. cPLA2 activity is also calcium-dependent; in

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addition, Ca2+ binding induces translocation of cPLA2 from the cytosol to the perinuclear membranes [154]. The Ca2+-independent PLA2 (iPLA2) or group VI enzyme, shares characteristics with the sPLA2 and with the cPLA2. iPLA2 exhibits no apparent substrate specificity for AA containing phospholipid. iPLA2 shares the size (85 kDa), intracellular localization, and possibly elements of the catalytic mechanisms with cPLA2. A distinctive element of the iPLA2, in addition to the absence of a Ca2+ requirement, is that it contains eight ankyrin motifs at the N-terminus half of the molecule which favors its activation by oligomerization [155–158]. The PAF acetylhydrolase (PAF-AH) or group VII catalyzes hydrolyis of the sn-2 ester bond of PAF and related proinflammatory phospholipids and thus attenuates their bioactivity. PLA2s are present in the retina [7,104,159,160]. The distribution of phospholipase activity was reported to be present in retinal lysosomes, microsomes, mitochondria, and in rod outer segment membranes (ROS) [161,162]. Calcium independent and calcium dependent PLA2 activities have been found in these ROSs and PLA2 exhibits a preference for phosphatidylcholine and phosphatidylethanolamine substrates enriched in PUFA. The sPLA2-IB location was described in the inner photoreceptor layer, the plexiform layers, the cytoplasm of the ganglion cells, as well as the RPE. The existence of genes encoding six subgroups of sPLA2 (sPLA2-IB, -V, -X, -IIE, -IIA, and -IIF) in mammalian (rat) retina was recently shown; differences in expression are observed such that for instance sPLA2-X exhibits lower expression than other sPLA2s [163]. In retinal ROS protein phosphorylation (by protein kinase C and protein kinase A) and dephosphorylation modulates PLA2 activities in isolated ROS [164]. Evidence has accumulated to suggest that PLA2 is activated by G-proteins. The predominant changes in expression of specific PLA2 such as sPLA2-X during certain photic-induced retinal injuries suggest particular roles during pathophysiological conditions. The type of PLA2 modulated during ischemic proliferative retinopathies has yet to be determined. All in all, PLA2 is a key class of enzymes involved in the generation of important lipid mediators, of notable relevance in this review, prostanoids, prostaglandin-like isoprostanes and PAF. The following sections discuss how these three classes of potent inflammatory lipid mediators partake in an interactive as well as a sequential cascade in the pathogenesis of ischemic vasoproliferative retinopathy. 4.2. Arachidonic acid-derived bioactive mediators 4.2.1. Prostanoids Upon reperfusion, oxidative products of AA, namely the prostanoids, which include the prostaglandins and TXA2, prolong and contribute to the ischemic insult by

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compromising blood flow, potentiating neutrophil adhesion and inflammation to the endothelium, and causing capillary oedema by increasing vascular permeability [165]. This section is intended to highlight advances made over the past years in understanding prostanoid synthesis, signaling, and vasomotor effects in the retina under basal and ischemic conditions. 4.2.1.1. Prostaglandins and TXA2 synthesis from AA by cyclooxygenases. Great progress has been made in describing the synthesis of most known prostanoids by retinal tissues [3,166–169]. COX catalyzes the first steps in prostaglandin, thromboxane and prostacyclin synthesis. Once AA has been liberated, it is converted by COX to the cyclic endoperoxide, PGG2, via an intermediate radical. Then, the COX peroxidase activity generates PGH2 from PGG2. The next prostanoid produced from PGH2 is largely dependent on the enzymes produced by the retinal cell and may generate five different prostanoids (PGD2, PGE2, PGF2a, PGI2, and TXA2 [170]. COX enzymes are membrane-bound hemoproteins and include two isozymes encoded from two separate genes, COX-1 and COX-2, which share similar enzyme kinetics [171,172]. In the retina, COX-1 and COX-2 activities contribute equally to the production of neonatal prostanoids [3,173,174]. Almost ubiquitously expressed, COX-1 is the constitutive form that is responsible for the low prostaglandin synthesis required for cell homeostasis while the inducible form, COX-2, is synthesized de novo in response to a wide range of extracellular and intracellular stimuli in the course of inflammation or other cellular stresses. Both COX-1 and COX-2 are located on the luminal surface of the endoplasmic reticulum and in inner and outer nuclear membranes [23,24,170,175]. In the retinal tissue, COX-2 is abundantly present in synaptic regions of human, mouse, and rat [6]. Oxidative stress such as ischemia-reperfusion in the retina results in increased formation of ROS, and in turn augments the synthesis of AA-derived prostanoids [31,110,176,177]. Catalysis of PGH2 formation by COX involves a radical at the active site on tyrosine at position 385 which needs to be regenerated by peroxides during the peroxidase step for continued activity of the enzyme. In the usual setting, the endoperoxide PGG2, can serve as the electron donor resulting in PGH2 formation to generate the tyrosyl radical and in turn initiate COX activation [148,178]. Indeed, COX has been shown to generate peroxides to a significant extent in the retina and peroxidation contributes significantly to the development of ROP [3,143,179]. The peroxides favor TXA2 production over that of prostaglandins [43,110] because of inherent characteristics of TXA2 synthase and reductive cofactor requirements (glutathione and NADPH) for PGI2, PGE2, PGD2 and

PGF2a synthases. The decreased ability of the newborn to dispose of ROS, perhaps, could favor a greater activation of TXA2 synthesis by peroxides in the neonatal subject. Because ischemia precedes angiogenesis, a potential mechanism by which retinal neovascularization associated with retinopathy of prematurity might occur is by a peroxide-induced generation of the potent vasoconstrictor and microvascular cytotoxic agent, thromboxane (see below). The pathogenesis of ischemic retinopathies is also associated with microthrombosis and proinflammatory changes and altered expression of several genes involved in apoptosis. Following the vasoobliterative phase, preretinal neovascularization sets in. Although VEGF plays a dominant role in this latter process, other mechanisms have also been suggested to facilitate the effects of VEGF. Interestingly, recent elegant studies on local retinal oxygenation using functional magnetic resonance imaging fail to reveal neovascularization in hypoxic areas, and suggest that hypoxia per se may not be sufficient (albeit implicated) in triggering the impending neovascular phase [180]. COX-2 is one of the immediate-early gene products in the ischemic retina [181], and along with another relevant immediate-early gene product, namely microsomal PGE2 synthase-1, is induced in the nerve fiber layer of retinas of humans with diabetes and vascular obstruction, and in animals after the hyperoxic phase, hence during hypoxicischemic phases. In these instances, induction of COX2 occurs mostly in astrocytes. The latter release PGE2, which acts on cognate receptors on adjacent endothelial cells [6]. Consistent with the time-dependent and propitious localization of COX-2, molecularly distinct inhibitors of this enzyme, the o-acetoxyphenyl hept-2ynyl sulfide (APHS) and etodolac, markedly diminished preretinal neovascularization, whereas COX-1 inhibition was ineffective [6,182,183]. Moreover, administration of PGE2 by acting specifically on its EP3 receptor (see below) reversed the antiangiogenic effects of COX-2 inhibitors in the retina [184–186]. Interestingly, the angiogenic effects of EP3 were found to be elicited by suppression of the anti-angiogenic thrombospondin-1 and its receptor CD36, thus favoring the action of the major pro-angiogenic VEGF. Thus, during the vasoobliterative phase, possibly due to preferential coupling of COX-1 with TXA2 synthase, TXA2 generation is favored and in turn elicits vasoobliteration; whereas during the subsequent vasoproliferative phase, COX-2 is induced and through preferential coupling with microsomal PGE2 synthase leads to PGE2 formation which by acting on its EP3 receptor facilitates neovascularization [6,187,188]. 4.2.1.2. Prostanoids signal transduction. Prostanoids act on G-protein-coupled receptors classified as FP for PGF2a, DP for PGD2, IP for PGI2, TP for TXA2, and

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EP for PGE2. EP receptors have been further subdivided into EP1, EP2, EP3 and EP4 subtypes; in addition, 9 isoforms of EP3 have been cloned in humans. EP receptors, mainly of the EP3 subtype, are the most diverse of the prostaglandin receptors and are found in nearly every tissue. Activation of FP and EP1 receptors increases inositol 1,4,5-triphosphate (IP3) production and that of EP2, EP4 and IP increases adenosine 30 ,50 cyclic monophosphate (cAMP) formation. Stimulation of EP3 receptors may decrease cAMP formation or increase IP3 production [170,189]. The retinal microvasculature contains all prostanoid receptors with the exception of EP4. The retinal vascular effects of prostaglandin E2 (PGE2) are mediated mainly by EP1 and EP3 receptors. EP2 activation by PGE2 is relatively small which density is greater in adult than in newborn [190]. A decrease in retinal vasoconstriction to PGE2 and PGF2a in the newborn was found to be mostly associated with a reduction in corresponding receptors and receptor coupled second messengers when compared to the adult [166]. The neonatal deficiency in ocular FP, EP1 and EP3 receptors, which are coupled to vasoconstriction, was found to be secondary to their homologous down-regulation by high prostaglandin levels in the perinatal period. Consistently, in response to a rise in perfusion pressure, PGE2 and PGF2a are abundantly released by the ocular vasculature causing vasoconstriction in the adult whereas they exert negligible effects in the newborn [20,191]. However, inhibition of COX for 24 h in newborn animals results in an upregulation of PGE2 and PGF2a receptors, receptor-coupled transduction mechanisms and vasomotor response to values comparable to the adult, as well as an improvement in ocular blood flow autoregulation (Fig. 1A) [174]. 4.2.1.3. Effects of prostanglandins on the retinal circulation. The retina and its vasculature predominantly generate PGI2, rather than PGE2, which is generated by most other neural and nonneural tissues. Although, in general, the responses of the retinal vasculature resemble those of other surface neural vessels the retinal vasculature exhibits distinct vasomotor responses to a variety of agents, including prostanoids and peroxides. The vasomotor effects of prostanoids are dependent on their nature, the type of tissues, and their development [192]. Differential effects of some of the prostaglandins in the vasculature should also take into account their receptor types and couplings. As indicated above, retinal arteries and veins of newborn animals respond minimally to the vasoconstrictor PGE2 and PGF2a, in contrast to those of the adult [190,192-194]. However, newborn retinal arteries and veins contract markedly to the thromboxane receptor agonist U46619. Because PGE2 and PGF2a cause minimal vasoconstriction in newborn compared with adults, the balance of prosta-

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glandin action is shifted towards PGI2 and possibly PGD2-elicited relaxation [190,193]. On the other hand, PGI2 and PGD2 which are released to a lesser extent in adult, cause greater relaxation in the newborn. Interestingly, the agedependent difference in response to constrictor prostaglandins (PGE2 and PGF2a) is greater than that to dilators (PGI2 and PGD2). Hence, developmental divergence in the vasomotor and the vasoconstrictor actions of prostaglandins seem to contribute to the ontogenic differences in RBF autoregulation [4,21,41]. 4.2.1.4. Role of TXA2 in retinal microvascular degeneration. TXA2 exerts known functions that may play a role in vasoobliteration, especially platelet aggregation and vasoconstriction [195,196]. Platelet aggregation is involved in other forms of ischemic retinopathies [197]. Nevertheless, studies of oxidant stress on impaired ocular hemodynamics and on OIR reveal an early endothelial cytotoxicity that is independent of platelet aggregation, although this can be detected later [83,88,110,166,198–200]. The degree of retinal vasoconstriction evoked by TXA2 is unlikely to result in vasoobliteration, as supported by the effects of other important retinal vasoconstrictors such as PGF2a, which are equally released under oxidant stresses but did not cause cell death [110,190]. Hence, effects of TXA2 on endothelial cytotoxicity independent of platelet aggregation and vasoconstriction probably also contribute to the retinal vasoobliteration associated with OIR. Indeed, inhibition of TXA2 formation or action preserved retinal microvascular integrity in the OIR model (Fig. 2A) [201]. In addition, TXA2 generation caused a timeand concentration-dependent cell death of retinovascular endothelial cells while other primary prostanoids did not cause cell death [201]. Thromboxane-induced cytotoxicity to retinovascular endothelial cells was rather direct, rapid (p4 h) and relatively cell type selective [201,202]. This TXA2-dependent retinovascular endothelial cell death was found to be mostly by necrosis and to a lesser extent by apoptosis. The nuclear condensation and DNA fragmentation were observed in p8% of cells and inhibition of major effector caspases only slightly reduced TXA2 mimetic-induced cell death. On the other hand, the TXA2 mimetic U-46619 caused a timedependent increase in plasma membrane disruption (propidium iodide incorporation, and LDH release) suggestive of necrosis (Fig. 3A). Nonetheless, because of the relatively long lag time (24 h) between TXA2 mimetic treatment and detection of cell death, one cannot totally exclude a form of cell death intermediate between apoptosis and necrosis as proposed for other cells and termed necrapoptosis [203,204]. The mechanisms for TXA2-induced cytotoxicity of retinal vascular endothelial cells are in the process of

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Fig. 2. Representative retinal flatmounts in a rat model of hyperoxia-induced ischemic retinopathy. Effects of TXA2 synthase inhibitor CGS12970 (A), 8-iso-PGF2a (B), and PAF receptor antagonist BN52021 (C) on retinal microvascular density. Rats were exposed from postnatal days 514 to normoxia (21% O2) or hyperoxia (80% O2). On postnatal days 911, saline solution containing active treatment were injected daily into the preretinal vitreous of one eye of rats whereas the other eye received only the saline as control. Retinas were collected on day 15 and flat mounts were stained with adenosine diphosphate to detect microvasculature. Magnification: 35  ; scale bar is 500 mm. Note significant attenuation of the hyperoxia-induced retinal vasoobliteration by vitreous injection of the TXA2 synthase inhibitor CGS-12970 and the PAF receptor antagonist BN52021; in addition, retinal vascular degeneration elicited by 8-iso-PGF2a is prevented by CGS12970.

being explored. Increased cellular calcium mobilization and incorporation by TXA2 can induce both necrotic and apoptotic cell death processes [205]. Changes in cellular calcium can activate specific phospholipases and proteases, disrupt mitochondrial permeability transition pores, which results in arrest in ATP production, and

stimulate the generation of ROS, which can in turn sustain a self-destructive cycle [206–208]. Interestingly, we found that treatment of retinovascular endothelial cells with U-46619 caused a fourfold increase in hydroperoxides and, more importantly, the induced cell death was prevented by the antioxidant U-74389G [181].

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Fig. 3. (A) Effects of TXA2 mimetic U-46619 on isolated retinal microvessels. Freshly isolated small retinal microvessels (p25 mm) were incubated without or with U-46619, and 48 h later stained with membrane permeable Hoechst 33342 or normally membrane impermeable propidium iodide (PI) which incorporates in cells with disrupted membranes. A larger proportion of cells treated with U-46619 incorporate PI, reflecting disruption of cell membrane indicative of cell death. (B) Effects of 8-iso-PGF2a on thromboxane generation and cellular viability in isolated retinal microvessels. 8-isoPGF2a caused a rapid increase in the stable TXA2 metabolite, TXB2, which is inhibited by TXA2 synthase inhibitor CGS12970. (C) Retinovascular endothelial cells death induced by 8-iso-PGF2a is significantly prevented by the TXA2 synthase inhibitor CGS12970.

In summary, TXA2 has an important role in the retinal microvascular degeneration of OIR. During oxidative stresses, TXA2 is generated more abundantly in the newborn than in the adult. In addition, TXA2-induced constriction is more pronounced in fetus and newborn than in adult. TXA2 has been found to mediate the effects of major stable products of peroxidation, the isoprostanes (to be discussed in Section 4.2.2). TXA2 may contribute to this process by directly inducing retinovascular endothelial cell death. These compromising actions of TXA2 are further facilitated during oxidant stresses, especially in the immature subject relatively devoid of antioxidants. Collectively, findings support a role for TXA2 in microvascular endothelial degeneration associated with ROP and likely other ischemic retinopathies. 4.2.2. Prostanoid-like isoprostanes Isoprostanes are a family of compounds produced from AA via a free-radical-catalyzed mechanism [209].

At present, 4 series of AA-derived isoprostanes have been discovered: F2-, E2-, D2- and thromboxaneisoprostanes. An abundantly produced isoprostane in vivo is 8-iso-prostaglandin F2 (8-iso-PGF2a) (or 15-F2tisoprostane) and, in view of its commercial availability, the one most studied has been 8-iso-PGF2a [210]. In contrast to prostaglandins synthesized by COX, the isoprostanes are formed in situ on esterified phospholipids and are released in free form, presumably by phospholipases. In oxidant stresses, formation of isoprostanes exceeds that of COX-derived prostaglandins. Numerous forms of isoprostanes are concomitantly generated during oxidative stress. The preferential increase of one form over another has been reported for isoprostanes containing different prostane rings. For instance, D2/E2 isoprostanes levels have been found to augment to a greater extent during hyperoxic stress than F2-isoprostanes [211]. In the mammalian retina, 15-F2t-isoprostanes and its metabolite (2,3-dinor-5,6-dihydro-15-F2t-IsoP) evoke

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vasoconstriction by stimulating TXA2 formation from neurovascular cells (Fig. 3B) [64]). Equivalent inhibition of the constrictor effect of 8-iso-PGF2a by the PLA2 blocker OPPC, the COX inhibitor indomethacin, and the thromboxane synthase inhibitor CGS-12970 suggests that 8-iso-PGF2a acts on the synthesis of thromboxane, rather than on its receptors, by stimulating the release of AA, which is metabolized by COX into prostanoids of which thromboxane dominates in importance. In addition, the data suggest that 8-iso-PGF2a elicits retinal vasoconstriction by releasing endothelin and more importantly the prostanoid thromboxane from retinal parenchymal and endothelial cells after Ca2+ entry into cells possibly through non-voltagedependent Ca2+ channels [64,212]. The commonality of this mechanism of action of these isoprostane isomers might suggest (but not prove) that they all may exhibit actions via a similar receptor pathway, which seems to involve that of the TXA2 receptor, consistent with the requirement of this receptor to mediate most vasomotor effects evoked by F2-isoprostanes; on the other hand the molecular identity of the binding site of isoprostanes has yet to be identified. A potential role for 8-iso-PGF2a in retinal microvascular cell death was recently proposed. 8-Iso-PGF2a was found to cause cell death of isolated retinal microvasculature (p25 mm) (Fig. 3C). A similar vascular degeneration was also detected by injecting in vivo into the preretinal vitreous 8-iso-PGF2a in young rat pups (Fig. 2B). The mechanisms of this cell death seem largely mediated by TXA2 [201]. Altogether, isoprostanes not only compromise retinal circulation by diminishing blood flow, but also seem to contribute to the oxidant stress-induced vascular injury as seen in ischemic retinopathies. Since isoprostanes reproduce many effects of oxidant stress, they may serve as mediators in peroxidation-induced actions. Data suggest that the effect of 8-iso-PGF2a on retinal vasculature is mediated mostly by cyclooxygenasegenerated formation of thromboxane and, to a lesser extent, by endothelin, probably through non-voltagegated cation channels. Because isoprostanes are produced in the retina during oxidant stress, it is possible that 8-iso-PGF2a may contribute to the pathogenesis of ischemia-reperfusion retinal injury such as in ROP and diabetic retinopathy. 4.3. Platelet-activating factor 4.3.1. PAF biosynthesis PAF, an 1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine, is a biologically active membrane-derived phospholipid mediator able to exert both physiological and pathological responses at picomolar and nanomolar concentrations. PAF is not stored in a preformed state but is rather rapidly synthesized in a highly regulated

fashion by cells or tissues in response to a cell-specific stimulus. Cells and tissues that synthesize PAF include endothelial cells from all vascular beds, leukocytes, platelets, lungs, and brain [213–217]. Many PAFmolecular species are generated either by enzymatic controlled synthetic reactions or from uncontrolled reactions of oxidative fragmentation of PUFA to PAF-like lipids. The structural requirements for biological activities of PAF are highly specific and the lipid structure that possesses the most activity is the alkyl palmitic form. PAF may be synthesized via two synthetic pathways namely, de novo or remodeling pathway. The de novo pathway is thought to maintain basal levels of PAF under unstimulated conditions and to maintain normal cellular function. Therefore, it is responsible for the constitutive synthesis of PAF and is regulated only by the availability of substrates. As the name implies, the de novo pathway synthesizes newly generated phospholipids in three enzymatic steps. On the other hand, the remodeling pathway is mainly involved in the calcium-dependent synthesis of PAF by stimulated cells, such as inflammation, in two enzymatic steps. This pathway involves a chemical modification in the structure of a pre-existing molecule associated with cellular membranes. The activation of cPLA2 by calcium catalyzes the hydrolysis of 1-alkyl-2-arachidonoylglycero-phosphocholine at the sn-2 position to yield the immediate PAF precursor 1-alkyl-sn-glycero-3phosphocholine (lyso-PAF) and free fatty acid usually arachidonic acid. Lyso-PAF is then acetylated by a specific lyso-PAF acetyltransferase using coenzyme A as a donor to give rise to biologically active PAF. Evidence from cPLA2 knock-out mice show that the activation of the cPLA2 enzyme is essential for triggering the remodeling pathway and in generating lyso-PAF [218,219]. The ratio of PAF produced enzymatically versus nonenzymatically is unknown although this would probably depend on the cell type and the time exposure to the source of oxygen radicals. Furthermore, given the unstable nature of PAF it is often problematic to measure these molecules in vivo. 4.3.2. PAF precursors in retina Choline phosphoglycerides are the precursor of PAF. In the intact retina and in the neural retina, the alkylacyl-glycero-3-phosphocholine and alkenylacylglycero-3-phosphocholine comprise 1.2% and 1.5%, respectively, of the total choline phosphoglycerides, whereas the rod outer segments contain twice the proportion of the precursor of PAF and no detectable plasmalogens (1-O-alk-1’-enyl-2-acyl glycerophospholipids). On a mole percent basis, AA was higher in neural retinal alkenylacyl-glycero-3-phosphocholine (27%) compared to alkylacyl-glycero-3-phosphocholine (18%)

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and diacyl-glycero-3-phosphocholine (5%). However, alkylacyl-glycero-3-phosphocholine from rod outer segments was enriched in docosapentaenoic acid (18%) while arachidonic acid was in the 3–4% range. In the neural retina, alkyl-arachidonoyl-glycero-3-phosphocholine is a source of both PAF and AA which may contribute to inflammatory episodes in retinal pathology [220]. 4.3.3. PAF signal transduction PAF acts via a single specific receptor that is a member of the family of G-protein coupled seven transmembrane receptors, PAFR [221,222]. PAFRs are distributed on platelets and numerous cells, notably leukocytes, smooth muscle, and endothelium [223]. PAF has been reported to transmit paracrine and autocrine signals and in some systems, intracrine signals reflecting the many physiological and pathological responses exerted by this lipid mediator [214,221,223–229]. The potency of PAF, its broad actions, and the potentially deleterious events associated with its signaling, together invoke the rationalization of a tight regulation of PAF synthesis [230]. 4.3.4. Effects of redox-activated PAF in retinovascular degeneration PAF is abundantly generated after oxidant stress and contributes to retinal neurovascular injury [223–228]. PAF also has a synergic effect on oxidant stress by increasing the generation of oxygen radicals [231,232]. An important role for PAF in retinal vasoobliteration in OIR was recently suggested by the relative preservation of microvasculature (ADPase-positive) by molecularly distinct PAF receptor antagonists including BN52021 (Fig. 2C), CV-3988, PCA-4248 and THG315 [66]. A major finding was the direct and relative selectivity of PAF-induced cytotoxicity to retinovascular endothelial cells; umbilical, dermal, and aortic endothelial cells, and retinal pericytes were hardly affected. PAF evoked-toxicity was not only observed in vitro on cultured endothelial cells but also ex vivo on freshly isolated retinal microvessels (o30 mm, mostly endothelial cells) of distinct species (Fig. 4A and B). A similar PAF receptor density in retinovascular and umbilical vein endothelial cells could not explained an increased vulnerability favoring retinovascular endothelial based on a limited expression of PAF receptors in the other cell types tested [223]. Retinovascular endothelial cell death induced by PAF is not primarily due to apoptosis. Cells exposed to PAF did not present any DNA fragmentation (TUNEL) or caspase activity classically related to apoptotic cell death. However, cells presented propidium iodine incorporation and lactate deshydrogenase activity which are markers of major damages to the cell membrane and markers of necrosis. Nonetheless, because of the

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relatively long lag time (24 h) between PAF treatment and detection of cell death, one cannot totally exclude a form of cell death intermediate between apoptosis and necrosis, which has been termed necrapoptosis, (or programmed necrosis) as proposed for other cells [203,204]. 4.3.5. Interaction between PAF and prostanoids Some of the cellular effects of PAF could be mediated by AA metabolites generated after PAF-receptor interaction with the COX and lipoxygenase pathways [233,234]. The binding of PAF to its receptors initiates biochemical sequences that culminate in the release of additional lipid mediators. An arachidonoyl-dependent PLA2 is activated to release AA from membrane phospholipids, especially phosphatidylcholine and ethanolamine. AA is then predominantly metabolized by the cyclooxygenase pathway to prostaglandins F2a, E2 and D2, and TXA2. PAF intracellular actions may also induce transcription of COX, presumably the ‘inducible’ form COX-2. Both vasomotor and cytotoxic effects of PAF in the developing subject seem to be mediated to a large extent by TXA2 [66,235]. Thus PAF which is generated concomitantly with TXA2 during an oxidant stress, and also amplifies formation of the latter, seems to directly contribute to the retinal vasoobliteration in ischemic retinopathies (Fig. 4B). 4.4. Lipid mediator intracrine signaling through nuclear receptors The mechanism of action of lipid mediators (e.g., prostanoids and PAF) and lipid signaling molecules arising from their activities is thought to be primarily dependent on their interaction with specific cell surface receptors that belong to the heptahelical transmembrane spanning G protein-coupled receptor (GPCR) superfamily. Interestingly, accumulating evidence supports a perinuclear/nuclear localization of GPCR where they can modulate gene expression through a series of biochemical events [175,196,223,236–244]. Despite the growing evidence that establishes GPCRs at the cell nucleus, nuclear receptor activity has only been described for only a few, including endothelin and angiotensin II [23,24,238,245–248]. We will briefly summarize this novel concept related to nuclear GPCRs stimulated by lipids; extensive reviews already document this concept [175,243,249]. 4.4.1. Localization of functional prostaglandin E2 receptors in the nuclear envelope There is compelling evidence for the existence of nuclear GPCRs of lipidic ligands, namely for PGE2 receptors (EP1, EP3a and EP4) in a variety of cells and tissues, in both newborn and adult animals [23,24]. Radioligand binding studies revealed that the kinetics of

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Fig. 4. Prevention of C-PAF-induced microvascular cytotoxicity by PAF receptor antagonist and thromboxane synthase inhibitor. (A) Isolated retinal microvessels (p25 mm, largely composed of endothelium) from 15 days old rats were incubated for 24 h with C-PAF; Hoechst 33342 stains nuclei of all cells, whereas PI stains nuclei of dying cells with disrupted plasma membrane. Incorporation of PI was prevented by pre-incubation with PAF receptor antagonist CV-3988. (B) A comparable preservation of retinal endothelial viability was observed by inhibiting TXA2 synthase using CGS12970 in cells exposed to PAF.

PGE2 binding to plasma membrane and nuclear membrane fractions isolated from pig newborn brain, adult uterus, and adult rat liver were similar; these tissues are known to express high levels of PGE2 receptors. However, in each tissue, the relative distribution of EP receptors in plasma membrane and nuclear membrane differed. A perinuclear localization of EP1, EP3a and EP4 receptors was visualized by indirect immunocytofluorescence in cultured porcine newborn cerebral microvascular endothelial cells, in transfected human embryonic kidney (HEK) 293 cells over-expressing these receptors, in fibroblast Swiss 3T3 cells overexpressing EP1 receptor and in HEK 293 cells expressing EP1 receptor fused to green fluorescent protein. High resolution immunostaining of EP1, EP3a and EP4 receptors revealed their presence in the nuclear envelope of cultured porcine endothelial cells and in situ in adult rat brain (cortex) endothelial cells and neurons (Fig. 5a and b) [23,24]. Physiological relevance of functional perinuclear prostanoid receptors is strengthened by localization of ligand-generating enzymes, namely cPLA2, COX-1, and COX-2, in the vicinity of receptor sites at the nuclear envelope [115,250]. The nuclear membrane EP receptors were found to increase the transcription of two target genes (iNOS, c-fos), that are known to be stimulated by PGE2. Nuclear calcium transients were also modulated by stimulation of nuclear EP receptors and this appears to involve pertussis toxin (PTX) -sensitive G proteins [23,24]. Of importance, a recent study identified for the first time distinct functional roles for the nuclear envelope G protein-coupled EP3 receptor from those on plasma membrane. The nuclear EP3 receptor was

found to regulate expression of the major constitutive gene for endothelial nitric oxide synthase (eNOS) via a PTX-sensitive EP3, which involves activation of formely undescribed perinuclear Ca2+-dependent K+ channels as well as phosphatidylinositol 3-kinase, MAP kinase kinase, and NF-kB pathways [251]. In contrast to the nuclear EP3 receptor, the one at the plasma membrane exerted distinct functions, notably acute vasoconstriction. The presence of functional nuclear EP3 receptors that regulate eNOS expression provides an unprecedented explanation as to developmental perinatal changes and hypercapnia-induced modulation of eNOS expression mediated via nuclear EP3. 4.4.2. Nuclear functional platelet-activating factor receptors Since PAF is a potent inducer of COX-2 we proceeded to investigate if this transcription was also mediated via activation of its cognate nuclear PAF receptor. This rationale was based on evidence that the majority of newly generated PAF was retained within cells. Indeed, confirmation of existence of other functional lipid-stimulated GPCRs, namely for PAF as well as lysophosphatidic acid, has recently been disclosed [240,252]. Isolated nuclei from microvascular endothelial cells were found to generate PAF-molecular species in response to H2O2. Using multidisciplinary approaches (flow cytometry, nuclear radioligand binding studies, immunoblotting, confocal microscopy), in porcine brain microvascular endothelial cells, PAF receptors were shown to co-localize both at the nuclear envelope and inside the nucleus [252] and Fig. 5d and e) Furthermore, in situ localization

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Fig. 5. Nuclear localization of functional prostaglandin E2 receptors EP3 and PAF receptors. EP3 immunolocalization on cerebral endothelial cells plasma membrane (a; arrow) and nuclear envelope by electron microscopy (b;arrow) (bar ¼ 0.5 mm). (c–f) In situ ultrastructural detection of PAF receptors on (porcine) neuroretinovascular endothelial cells by electron microscopy. PAF receptor immunoreactivity is detected on plasma membrane (c,e; arrows), nuclear membrane (d; arrowheads), as well as in the nucleus (e; arrows); panel (f) is a control, whereby there is absence of immunogold labeling when the anti-PAF recetor Ab is incubated with its cognate peptide. L, lumen of blood vessel; N, nucleus.

determined by immunogold electron microscopy revealed receptor expression both at the nuclear envelope of endothelial cells and neurons as well as at the nuclear matrix mostly confined to euchromatin structures.

Comparable immunoreactivities and molecular masses for receptors at the plasma membrane and on isolated nuclei suggested that PAF receptors at the nucleus are intact entities similar to those at the plasma

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membrane (Fig. 5c). Despite receptor similarities, separate functions for the intracellular and cell surface receptors have been suggested using agents that putatively distinguish these receptors [253,254]. Specifically, immediate effects have been proposed to be mediated by cell surface receptors, whereas regulation of expression of specific genes may be dependent upon intracellular receptors, consistent with the presence of signaling effectors in nuclei, including G proteins, ionic channels, phospholipases, adenylate cyclase, kinases, and NF-kB [250,255–262]. Recent observations unequivocally confirmed distinct signaling mechanisms between the cell surface and nuclear PAF receptors such that the surface receptor was coupled to Gaq and that at the nucleus interacted with Gai [252]. Finally, stimulation specifically of the nuclear PAF receptor was found to induce transcription of major pro-inflammatory genes involved in the pathogenesis of ROP, namely COX-2 and iNOS.

synthase, resulting in the generation of thromboxane from retinal parenchymal and endothelial cells. But oxidized AA are readily cleaved off phospholipids to yield lysophospholipid which in turn can be acetylated and converted to PAF. The latter mediator also exerts endothelial cytotoxicity and thus amplifies effects of isoprostanes. Finally the discovery of nuclear GPCRs for prostaglandin and PAF receptors provides a novel mechanism of GPCR signaling specifically a pathway operating within the nucleus rather than having a seemingly less direct and more unwieldy molecular mechanism which would transfer signal from the cell surface to the cell’s interior. In addition, distinct localization of GPCRs may dictate different mechanisms for the same receptor to manifest its various functions. Plasma membrane receptors elicit acute responses while nuclear receptors would participate in the intracrine mode of actions of phospholipids in regulating gene transcription.

4.5. Summary

4.6. Perspective-factors promoting endothelial cell survival during vasoobliteration

Besides to their well-known conservatives roles as structural elements (amphiphilic lipids of the cell membranes) and as energetic reserve (essentially triglycerides), a number of lipids function as ‘‘second messengers’’. The addition of oxygen to lipids is an important process developed by biological systems to generate a wide spectrum of compounds both by enzymatic and non-enzymatic mechanisms. The abundant content of unsaturated fatty acids in the retina makes this tissue particularly susceptible to peroxidation. Lipid peroxidation exerts a significant role in the genesis of several retinopathies, such as ROP and of diabetes. Peroxide-induced activation of COX, resulting in the generation of thromboxane, compromise retinal hemodynamics circulation (partly TXA2-dependent) and vascular architecture and integrity by causing marked vasoconstriction leading to ischemia, which in turn alters retinal function and predisposes to neovascularization (Fig. 6). In addition, in the perinate, COX activity is high, and as a result produces increased levels of prostaglandins. The increased production of prostaglandins in the perinate augment ocular blood flow and results in an excess increase in oxygen delivery to an immature retina partly devoid of antioxidant defenses. The ensuing peroxidation leads to ischemia which predisposes to abnormal preretinal neovascularization, a major feature of ischemic retinopathy. The stable products of peroxidation, the biologically active isoprostanes and possibly others such as the isofurans and isoketals reproduce effects of peroxidation. The isoprostanes elicit not only a potent retinal vasoconstriction but also cytotoxicity predominantly by activating the COX pathway and particularly TXA2

Different vascular beds may have specific survival mechanisms that could prevent degeneration of endothelial cells in the vasculature. It appears that genetic and epigenetic factors influence the susceptibility and severity of ischemic retinopathy development in a proportion of cases [263,264]. An interindividual heterogeneity in the expression of anti-inflammatory and cytoprotective mediators may be possible. Indeed, different strains of the same species will develop variable retinopathy to the same stimulus. What are the prospects of therapeutic agents in the case of ROP, particularly the initial phase of vasoobliteration? Considering the defined nature of the pathogenic insult, its relatively short duration (vessels in ROP need to be protected only during the period spent during the relative hyperoxygenation), its predetermined onset, and in conjunction with the facts that the vitreous is a close, immunoprivileged compartment and that the superficial retinal vessels are accessible to injected reagents, the likelihood of success is high. A role for growth factors has recently been implicated in the development of the initial crucial phase of ROP [265]. Transgenic mice, engineered to be insulin-like growth factor-1 deficient, experienced retarded vascular development at a postnatal age of 5 days. It was hypothesized that preterm infants incapable of producing this growth factor may be more prone to developing the destructive neovascular second phase. But what is the interplay of such growth factors and lipid mediators? This critical aspect needs investigation. In vitro studies on the retinal vasculature, have shown that some antioxidants reduce vascular retardation and leak, while preventing vessel vaso-obliteration.

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Fig. 6. Interaction between excess O2 and inflammatory lipid mediators in ischemic retinopathy. Schematic representation of the interaction between oxidative stress, the pro-inflammatory cyclooxygenase-2 (COX-2), thromboxane A2 (TXA2), isoprostanes, and platelet-activating factor (PAF) in retinal vasoobliteration and microvascular degeneration associated with ischemic retinopathies. Upon stimulation of cell membranes, a biosynthetic cascade that stems from the action of cytosolic phospholipase A2 (cPLA2) enzyme, releases arachidonic acid (AA) and immediate precursors for isoprostanes and PAF. Major prostanoids, prostaglandins (PG) and TXA2, are derived from AA through a preliminary step catalyzed by COX. PAF and TXA2 both can induce significant neuroretinovascular endothelial cytotoxicity. The mechanism of action of lipid mediators is primarily dependent on their interaction with cell surface G protein-coupled receptor (GPCR) superfamily. Evidence supports a perinuclear/nuclear localization of GPCR where they can modulate gene expression involved in the cell death process through a series of biochemical events. Immediate effects have been proposed to be mediated by cell surface receptors, whereas regulation of expression of specific genes may be dependent upon intracellular receptors. The abbreviation TXS and TP refer respectively for thromboxane synthase and thromboxane A2 receptor.

However, meta-analyses of randomized studies of antioxidant supplementation in the prevention of ROP have produced conflicting results [111,266]. There are many possible reasons for the discrepancies observed between pre-clinical studies and clinical practice. These include inadequate drug delivery, use of a very brief and non realistic time frame (cellular distribution, kinetics and efficacy of compounds), but mostly leaving the door open for the other processes to produce excitotoxicity, or an inadequate activation of endogenous anti-inflammatory mediators. An alternative approach to growth factor and antioxidant administration is the use of mimetics that activate the relevant signal transduction pathways. Thromboxane directly induces retinal endothelial cell

death and increases retinal vessel constriction which ultimately contribute to the microvascular degeneration in ROP models. The prostaglandin synthase inhibitor indomethacin has been shown to reduce vessel constriction probably by reduction of thromboxane. However, in clinical studies, prophylactic treatment with indomethacin did not alter the incidence of ROP likely because of its early and limited timing of administration [267,268]. On the other hand, targeting more specifically receptors that convey cytotoxicity (e.g. TXA2 receptor antagonist) and/or cytoprotection (e.g. EP3 receptor agonist) may be more promising [6,66,201]. Along the same lines, intracellular compartmentalization of GPCRs exhibiting distinct functions may also have important pharmacological consequences. By

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elucidating functional nuclear GPCRs, site-targeted drug design could be foreseen. In conclusion, the challenge is considerable to identify the efficient and well-tolerated prophylactic treatment of ROP. However, therapeutic strategy involving blockade of the signaling mediated by inflammatory bioactive lipids represents an interesting option which deserves to be more deeply investigated.

Acknowledgements Supported by grants form the Canadian Institutes of Health Research, the Hospital for Sick Children Foundation, the March of Dimes Birth Defects Foundation, the Heart & Stroke Foundation of Que´bec, the Fonds de la Recherche en Sante´ du Que´bec. MB is a recipient of a studentship awards from the Canadian Institutes of Health Research. FS is supported by a fellowship from the Deutscher Akademischer Austauschdienst. BM is a recipient of a studentship award from the Foundation Fighting Blindness of Canada. FjrG is a recipient of a scholarship from the Fonds de la Recherche en Sante´ du Que´bec. Pierre Hardy is a recipient of a Scientist awards from the Hospital for Sick Children Foundation, and awardee of a scholarship from the Fonds de la Recherche en Sante´ du Que´bec. SC holds a Canada Research Chair.

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