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British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 2018 Nov 19;176(1):93–109. doi: 10.1111/bph.14507

Bioactive lipids and pathological retinal angiogenesis

Khaled Elmasry 1,2,3,6, Ahmed S Ibrahim 1,4,5, Samer Abdulmoneim 1,2, Mohamed Al‐Shabrawey 1,2,3,5,✉
PMCID: PMC6284336  PMID: 30276789

Abstract

Angiogenesis, disruption of the retinal barrier, leukocyte‐adhesion and oedema are cardinal signs of proliferative retinopathies that are associated with vision loss. Therefore, identifying factors that regulate these vascular dysfunctions is critical to target pathological angiogenesis. Given the conflicting role of bioactive lipids reported in the current literature, the goal of this review is to provide the reader a clear road map of what has been accomplished so far in the field with specific focus on the role of polyunsaturated fatty acids (PUFAs)‐derived metabolites in proliferative retinopathies. This necessarily entails a description of the different retina cells, blood retina barriers and the role of (PUFAs)‐derived metabolites in diabetic retinopathy, retinopathy of prematurity and age‐related macular degeneration as the most common types of proliferative retinopathies.

Abbreviations

AA

arachidonic acid

AMD

age‐related macular degeneration

BRB

blood retinal barrier

CYP

cytochrome P450

DHA

decosahexaenoic acid

DHETs

dihydroxyeicosatrienoic acids

DR

diabetic retinopathy

EETs

epoxyeicosatrienoic acids

EPA

eicosapentanoic acid

HETE

hydroxyeicosatrienoic acids

IGF‐1

insulin‐like growth factor‐1

LA

linoleic acid

LO

lipoxygenases

PUFAs

polyunsaturated fatty acids

ROP

retinopathy of prematurity

RPE

retinal pigment epithelium

Introduction

The purpose of this review is to provide the reader with a clear summary of what has been accomplished so far in the field of bioactive lipids in pathological retinal angiogenesis with specific focus on the role of polyunsaturated fatty acids (PUFAs)‐derived metabolites in proliferative retinopathies. This necessarily entails a description of different retinal cells, blood‐retina barriers and the role of PUFA‐derived metabolites in diabetic retinopathy (DR), retinopathy of prematurity (ROP) and age‐related macular degeneration (AMD)as the most common types of proliferative retinopathies.

Retinal cell layers

The retina is the light‐sensitive part at the back of the eye, which converts the light signals into electrical signals (Figure 1). The retina can be divided anatomically into two parts: (i) central retina (also known as the macula) which is located in adult human retina nearly 3 mm temporal to the optic disc and is about 1.5 mm in diameter with a central depression called the fovea representing the area of maximum visual acuity. The fovea is dependent on choriocapillaries for its blood supply as it is devoid of retinal capillaries, (ii) the remaining part of the retina is called the peripheral retina (Kolb, 1995b). The main cellular components of the retina are the retinal pigment epithelium, the photoreceptors, the interneurons, the ganglion cells, the glial cells and the vascular cells.

Figure 1.

Figure 1

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Anatomy of the eye and organization of retinal layers. The eye is divided into anterior and posterior parts. The vitreous and the retina occupy the posterior portion of the eye. Retinal branches of the central retinal artery that enters the eye within the substance of the optic nerve ramify on the vitreal side of the retina to form the retinal circulation. The magnified part is to show that the retina is formed of more than one layer.

The retina is arranged into 10 layers, which are described from outside inward:

  1. Retinal pigment epithelium (RPE): Those are hexagonal shaped cells forming a single layered cuboidal epithelium, which is separated from the choriocapillaries by Bruch's membrane. The tight junctions between this epithelial monolayer constitutes the outer blood‐retinal barrier (BRB), which selectively separates the retinal photoreceptors from choroidal blood (Bonilha, 2014; Rizzolo, 2014).

  2. Photoreceptor layer: The light‐sensitive part of the retina in which the rods are responsible for dark vision (also known as scotopic vision) and the cones which are responsible for colour vision (also known as photopic vision); form a single layer of photoreceptors (Anderson and Fisher, 1976).

  3. Outer limiting membrane: It is formed by junctional complexes of neighbouring Müller cells in addition to the junctional complexes between Müller and photoreceptor cells (Omri et al., 2010).

  4. Outer nuclear layer: It is formed of the nuclei of the photoreceptor cells (Kolb, 1995b).

  5. Outer plexiform layer: It is the site of the synaptic connections between photoreceptor cells and the connecting neurones including the bipolar and horizontal cells (Brzezinski and Reh, 2015).

  6. Inner nuclear layer: It contains the nuclei of the horizontal, the bipolar, the amacrine, the inter‐plexiform and the Müller cells. They have a specific organization where the horizontal cells are closer to the outer plexiform layer; amacrine cells closer to the inner plexiform layer; while the bipolar, inter‐plexiform and Müller cells are in between (Kolb, 1995b).

  7. Inner plexiform layer: It is the site of the synaptic connections between bipolar and amacrine cells in the inner nuclear layer and ganglion cells in the ganglion cell layer (Kolb, 1995a, 1995b).

  8. Ganglion cell layer: It contains ganglion cells along with other cells, including some amacrine cells, pericytes, endothelial cells and astrocytes. The ganglion cells collect the visual information from the retinal photoreceptors and project these data to the parvocellular and magnocellular layers of the lateral geniculate nucleus of the brain. Due to the long distance between the retina and the brain, the axonal transport of the ganglion cells is highly active and requires ATP which is supplied by the active axonal mitochondria (Kolb, 1995a, 1995b).

  9. Nerve fibre layer: Axons of the ganglion cells collect in this layer travelling to the optic nerve head.

  10. Inner limiting membrane: The inner processes of Müller cells expand on the vitreal surface of the retina to form this membrane in which the collagen fibres of the vitreous are inserted. The inner limiting membrane maintains the compartmentation between retina and vitreous and is perforated by new blood vessels that invade the vitreous in proliferative retinopathies (Kolb, 1995a, 1995b).

Retinal glial cells

There are different types of glial cells in the retina including Müller cells, astrocytes and micoglia. Müller cells are the most numerous type of glial cells that exist in the retina (Reichenbach and Bringmann, 2013). Microglial cells are the retinal resident macrophages. They are derived from progenitor cells found in the yolk sac during early embryonic development (Kierdorf et al., 2013; Elmore et al., 2014).

Glial cells are highly important for the proper function of the retina. They display several important functions. They actively participate in the retinal‐blood barrier as their processes surround the blood vessels controlling the movement of different materials across the BRB. Moreover, they form sheaths around neuronal cells of the retina ensuring their interaction and support of the neural retina (Vecino et al., 2016). The ability of Müller cells to regulate the homeostasis of extracellular pH and K+ ions enables them to play a critical role in maintaining the integrity of the BRB. Müller cells and astrocytes regulate the extracellular space volume, metabolites clearance, K+ buffering and calcium‐related signalling, via the aquaporins, particularly aquaporin 4, which are located in their cell membranes (Lan et al., 2017).

Interestingly, glial cells are also involved in lipid metabolism. Thus, Müller glial cells may have a role in the intra‐retinal transport of lipids (Tserentsoodol et al., 2006). Also, Müller cells take up docosahexaenoic acid (DHA) (Gordon and Bazan, 1990), which is incorporated into glial phospholipids and finally transported to the photoreceptors (Politi et al., 2001). In addition, glial cells produce extracellular matrix (ECM) which contributes to the inner limiting membrane, providing a significant support for the retina (Clark et al., 2011; Keenan et al., 2012). These ECM components have a role in retinal angiogenesis as well (Jiang et al., 1994; Keenan et al., 2012).

One of the most important factors released by Müller cells is VEGF. Although basal levels of VEGF are neuroprotective, higher levels of VEGF are associated with vascular disorders (Zheng et al., 2012). VEGF can induce neuronal regeneration and angiogenesis after ischaemia/reperfusion injury (Ma et al., 2011) via direct activation of both neurons and endothelial cells (Oosthuyse et al., 2001). Apart from VEGF, glial cells synthesize other neurotrophic factors including pigment epithelium‐derived factor (PEDF) (Zhou et al., 2009; Unterlauft et al., 2012), brain‐derived neurotrophic factor (Dai et al., 2012), ciliary neurotrophic factor (Escartin et al., 2007) and glial cell‐derived neurotrophic factor (Harada et al., 2003; Hauck et al., 2006).

Retinal microglia may contribute to retinal inflammation, cell death and cell survival via their released cytokines (Schafer et al., 2013). Microglial cells are the major cellular component of the innate immunity system in the retina, and their activation is strictly regulated by different inhibitory pathways (Copland et al., 2010; Chen et al., 2012). Activated retinal microglia secrete mediators that affect the neural retina leading to increased neuronal apoptosis (Altmann and Schmidt, 2018). Hyperglycaemia and glycated albumin are among the main factors that activate retinal microglia during diabetes (Ibrahim et al., 2011). Prolonged activation of microglial cells in diabetic retina tends to be proinflammatory rather than anti‐inflammatory and thus can generate a state of chronic inflammation that may be related to retinal affection during DR (Arroba and Valverde, 2017). Prolonged stimulation of the diabetic retina by damage‐associated molecular patterns leads to dysregulation of the retinal innate immune system, which may contribute to development of DR. In the progressive stages of DR, recruited immune cells infiltrating the retina can participate in retinal chronic inflammation with subsequent retinal vascular and neuronal damage (Xu and Chen, 2017).

Blood supply of the retina

The retina has a double blood supply: the outer retina (RPE and the photoreceptors) is supplied by the choroidal circulation, while the inner retina is supplied by the retinal circulation. However, the fovea and the extreme peripheral retina are avascular and receive their nutrition via diffusion from the choroidal circulation (Delaey and Van De Voorde, 2000). The retinal capillaries are arranged in a laminar meshwork to guarantee satisfactory perfusion to all retinal cells. Retinal capillaries are formed of endothelial cells surrounded by pericytes at a ratio of 1:1 (Shin et al., 2014).

Retinal barriers

The BRB is divided into an inner and an outer BRB. The barrier is formed by tight junctions of endothelial cells, basal lamina and end‐feet of astrocytes (Yao et al., 2014). The inner BRB is formed by the tight junctions between the non‐fenestrated retinal endothelial cells, which are surrounded by the processes of pericytes and Müller cells. Retinal endothelium, pericytes and Müller cells together form the inner BRB which is critical for the nutrition and protection of the inner two‐thirds of the retina (Hosoya and Tachikawa, 2012). On the other hand, the outer BRB, which is important for homeostatic maintenance of the outer third of the retina, consists of the tight junctions of retinal pigment epithelial cells (Cunha‐Vaz et al., 2011; Campbell and Humphries, 2012). The barrier prevents water‐soluble molecules from entering the retina. The fenestrated choriocapillaris is permeable to macromolecules and does not appear to contribute importantly to the blood‐retinal barrier. Bruch's membrane, situated between the choriocapillaris and RPE, represents a diffusion barrier only to macromolecules. A greater oncotic pressure in the choroid than in the retina is generated due to the high protein permeability of the choriocapillaris which results in fluid absorption from the retinal extracellular spaces into the choroid. The blood retinal barrier is affected in retinal pathologies (Cunha‐Vaz et al., 2011; Campbell and Humphries, 2012).

Pathological states of retinal angiogenesis

A delicate balance between proangiogenic and antiangiogenic factors regulates retinal vascular haemostasis. Retinal hypoxia, ischaemia or inflammation, may disturb this balance to induce pathological neovascularization in DR, ROP and AMD (Campochiaro et al., 2016) (Figure 2). Pathological retinal and choroidal angiogenesis lead to vascular leakage, bleeding and fibrosis and ultimately significant visual impairment. Therefore, it is important to investigate the underlying cellular and molecular mechanisms of pathological retinal neovascularization (RNV) to identify new therapies to save and improve the vision in patients with DR, AMD or ROP (Dreyfuss et al., 2015; Campochiaro et al., 2016).

Figure 2.

Figure 2

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General mechanisms of pathological RNV. Retinal hypoxia is a key factor in mediating pathological RNV in AMD, proliferative diabetic retinopathy (PDR) and ROP. Retinal hypoxia develops due to accumulation of drusen and RPE dysfunction in AMD, and capillary degeneration in PDR and ROP. Retinal hypoxia induces HIF1α‐dependent transcription of several proinflammatory and proangiogenic factors such as IL6, the chemokines CXCL12 and CCL2, inducible NO synthase (iNOS), VEGF and IGF‐1. This ultimately causes development of new blood vessels or RNV. HIF, hypoxia inducible factor.

Diabetic retinopathy

DR is a neurovascular complication affecting the retina of diabetic patients and remains one of the most common causes of blindness, worldwide. World Health Organization has added diabetic retinopathy on the priority list of eye conditions that should be prevented or treated. On a global level, there were approximately 285 million diabetes patients in 2010 and nearly 100 million of those exhibited signs of diabetic retinopathy (Lee et al., 2015).

There is a strong association between chronic hyperglycaemia during diabetes and the development of DR, although the underlying mechanisms of this association are still ill‐defined. A number of biochemical pathways have been suggested as possible links between hyperglycaemia and diabetic retinopathy, including dysregulation of the polyol pathway, accumulation of advanced glycation end products, activation of PKC, increased expression of growth factors as VEGF and insulin‐like growth factor‐1 (IGF‐1), haemodynamic alterations, oxidative stress, ER stress, activation of the renin‐angiotensin‐aldosterone system, chronic inflammation and increased adhesion of leucocytes to the endothelium (Cheung et al., 2010).

Clinically, DR is classified into two types: non‐proliferative and proliferative. Non‐proliferative DR is characterized by microaneurysms (the earliest sign, reflecting the pericyte loss and consequent weakness of the micro‐vessels walls), micro‐haemorrhage, macular oedema (the main cause of visual impairment), vascular tortuosity and beading. On the other hand, proliferative DR is characterized by retinal angiogenesis, vitreous neovascularization, haemorrhage or retinal detachment (Duh et al., 2017; Iwase et al., 2017).

The development of RNV in DR results from enhanced apoptosis of pericytes and endothelial cells and subsequent capillary degeneration that creates relative hypoxia. This leads to up‐regulation of the key angiogenic factor VEGF.

The current treatment modalities of DR include tight glycaemic control, anti‐VEGF therapies, laser photocoagulation, corticosteroids and surgical removal of the vitreous. Tight glycaemic control is effective in reducing incidence of DR and progression (Diabetes et al., 2015). The long‐term beneficial effect of glycaemic control has been examined by two large studies: The Diabetes Control and Complications Trial (DCCT) in Type 1 diabetes (Diabetes et al., 2015, 1993) and the United Kingdom Prospective Diabetes Study (UKPDS) in Type 2 diabetes (UKPDS Group, 1998). Both DCCT and the UKPDS have demonstrated that tight glycaemic control that maintains the levels of HbA1c ≤7% reduced development and progression of DR, with the beneficial effects of tight glycaemic control persisting up to 10–20 years.

The gold standard for the treatment of DR is still laser photocoagulation. This procedure is used to treat macular oedema in non‐proliferative DR. In proliferative DR, pan‐retinal photocoagulation is used where the laser is applied to the whole retina, except for the macula (Evans et al., 2014).

The introduction of intravitreal injection of anti‐VEGF therapies has changed the goal of DR treatment from stabilization to improvement of vision. Anti‐VEGF therapies significantly improve the visual acuity of patients with diabetic macular oedema. There are four FDA approved anti‐VEGF drugs that have been used in the treatment of DR. The first is bevacizumab (with the trade name Avastin, from Genentech). It is a recombinant humanized anti‐VEGF monoclonal antibody. The second drug is ranibizumab (trade name is Lucentis, also from Genentech), which is a recombinant antibody fragment (Fab) against VEGF‐A. The third anti‐VEGF drug is aflibercept (trade name is Eylea or known also as VEGF Trap‐Eye, from Regeneron), which is acting as a VEGF‐receptor capable of binding to both circulating VEGF‐A and VEGF‐B. It has VEGF‐binding domains of VEGF receptors 1 and 2. The fourth drug is pegaptanib (Macugen, from Valeant,), which binds specifically to the main pathological VEGF isomer in the eye, which is the VEGF‐A165 (Osaadon et al., 2014; Vaziri et al., 2015).

Another treatment, intravitreal injection of synthetic corticosteroids including triamcinolone acetonide (Bressler et al., 2013), dexamethasone (Callanan et al., 2013) and fluocinolone (Pearson et al., 2011) has been associated with reduced progression of DR, particularly when combined with other lines of treatment (photocoagulation or anti‐VEGF). However, this procedure was associated with adverse effects such as cataract formation or glaucoma progression. But they were less associated with vitreous haemorrhage, retinal detachment or possibility of endophthalmitis (Sampat and Garg, 2010).

Lastly, the surgical removal of the vitreous (vitrectomy) is used in proliferative DR when vitreous haemorrhage or retinal detachment occurs. Vitrectomy improved visual acuity in patients suffering from diabetic macular oedema, with a low rate of postoperative complications (Diabetic Retinopathy Clinical Research Network Writing et al., 2010).

Taken together, the pathogenesis of DR is complex and multifactorial, which provide a strong rationale to use more than one line of treatment in the same patient to achieve a better response. Studies have shown that when intravitreal corticosteroids (Avitabile et al., 2005; Kang et al., 2006; Lam et al., 2007; Gillies et al., 2011) or anti‐VEGF (Nguyen et al., 2009; Elman et al., 2011; Lee et al., 2011; Mitchell et al., 2011) were used as a combined therapy along with retinal laser photocoagulation, the outcome was better with a more improved visual acuity in those patients who received the combined therapy. However, these therapies are invasive and directed mainly towards late stages of DR, after significant and irreversible damage has occurred. Hence, preventative strategies that address early pathological events and neuronal dysfunction are highly desirable. These therapeutic limitations have generated the need for novel therapeutic interventions.

Retinopathy of prematurity

ROP is a multifactorial neovascular disease that affects premature infants and leads to childhood blindness worldwide. The disease was first described in the 1940s and was attributed to the use of oxygen to resuscitate preterm infants (Terry, 1946; Patz et al., 1953; Ashton et al., 1954). Several clinical studies showed a significant decrease in the severity and incidence of ROP by limiting the use of oxygen in premature infants (Tin et al., 2001; Tin and Wariyar, 2002; Chow, Wright, Sola, and Group, 2003; Anderson et al., 2004).

Development of ROP occurs in two distinctive stages. The first stage begins with the oxygen‐induced impairment of normal retinal vascular development and capillary degeneration. This stage is accompanied by a significant decrease in retinal levels of VEGF and IGF‐1 suggesting that administration of VEGF or IGF1 during this stage could inhibit the development of the second neovascular stage (Smith, 2004; Villegas‐Becerril et al., 2006). Capillary degeneration and vaso‐obliteration that occurs during the first stage of the disease and the increased metabolic activity of the developing retina leads to a relative retinal hypoxia. The developing hypoxia prevents hypoxia inducible factors from degradation by prolyl hydroxylases leading to up‐regulation of number of downstream pro‐angiogenic genes including VEGF, angiopoietins and erythropoietin (Smith, 2004; Heckmann, 2008) (Figure 2). Thus, interruption of hypoxia‐induced signalling has been accepted as a therapeutic strategy to treat and prevent the progression of ROP. This includes the use of anti‐VEGF therapy.

To investigate the underlying molecular and cellular mechanisms of retinal neovascularization in ROP and, in turn, to identify potential therapeutic targets, several animal models have been developed. These models collectively known as oxygen‐induced retinopathy models (OIR). In a mouse model of OIR, newborn mice are exposed to high oxygen levels (75% O2) at postnatal day 7 (P7) for 5 days, during which retinal vaso‐obliteration occurs. This is followed by exposure to normal room oxygen level for additional 5 days during which pathological retinal neovascularization develops due to retinal hypoxia (Smith et al., 1994). In the rat model of OIR, pups are subjected to fluctuating levels of oxygen (Ricci, 1990; Ventresca et al., 1990; Zhang et al., 2000). The limitation of animal models of OIR is the use of pups but not preterm animals. Although the rat model of OIR is more representative of clinical changes in ROP, the mouse model of OIR is used more frequently than the rat model because it allows for the use of mice with specific knockout mutations.

Laser therapy to the avascular retina is the standard treatment for ROP. However, laser therapy has therapeutic limitations including, but not limited to, the risk of general anaesthesia to the premature infants (Filippi et al., 2013; Attachoo et al., 2014). Targeting angiogenic factors such as the VEGF (anti‐VEGF agents) either alone or combined with laser therapy carries the promise of optimizing the vision improvement in ROP. Bevacizumab is a recombinant humanized monoclonal antibody directed against the VEGF. The Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (ROP) study was a prospective, randomized, stratified, controlled, multicenter study (Mintz‐Hittner et al., 2011; Stahl, 2018) and the results suggested that inhibition of VEGF with bevacizumab might be beneficial in preventing retinal neovascularization. However, more studies are needed to make sure there are no long‐term side effects, particularly as VEGF plays a role as retinal neurotrophic factor (Park et al., 2014; Li et al., 2016). It is important to know anti‐VEGF therapy has a wider effect on the pathophysiology of ROP and may account for the late failures.

There are several other emerging therapeutic approaches including and not limited to the use of antioxidants. Our research has demonstrated that inhibition of NADPH oxidase as an approach to inhibit oxidative stress could be helpful in prevention of retinal neovascularization (Al‐Shabrawey et al., 2005). Furthermore, our recent studies have focused on 12/15‐lipoxygenase as a potential therapeutic target to prevent retinal neovascularization in the mouse model of OIR (Al‐Shabrawey et al., 2011). Moreover, ω‐3 fatty acids that can reduce phase 1 and phase 2 in the mouse OIR model are being investigated in human infants (Fu et al., 2015; Malamas et al., 2017).

Age‐related macular degeneration

AMD is a disease that affects primarily the macula and accounts for 7% of legal blindness worldwide (Bressler et al., 2003; Bourne et al., 2018). The increased ageing of the population worldwide is a key factor in increasing the number of patients with AMD which is expected to reach 196 million and 288 million by 2020 and 2040 respectively (Wong et al., 2014). This significant number represents a major progressive burden on health care systems.

The early stage of AMD is characterized by accumulation of drusen, underneath the RPE (Garcia‐Layana et al., 2017) followed by progression to the advanced stages with geographic atrophy and choroidal neovascularization (CNV). The pathological features of geographic atrophy include gradual loss of RPE cells, photoreceptors and the choriocapillaris (Holz et al., 2014). The neovascular AMD is characterized by CNV in which aberrant vessels grow from the choriocapillaris and invade the retina. The new vessels are susceptible to vascular leakage, bleeding and fibrosis leading to formation of macular scars and rapid loss of central vision compared to the atrophic or geographic AMD (Ferris et al., 1984).

The pathogenesis of AMD is multifactorial in which RPE dysfunction, inflammation, oxidative stress and angiogenic factors play essential roles. Age‐dependent impairment of the phagocytic and barrier function of RPE leads to accumulation of cytotoxic lipofuscin, extracellular debris (drusen) and CNV (Figure 2). Therefore, current and future therapies are based on targeting the inflammatory, oxidative stress and angiogenic signalling that drive pathological and functional changes in AMD (Cabral et al., 2017; Hernandez‐Zimbron et al., 2018).

Antiangiogenic drugs, laser therapy, vitamins and surgery alone or in combination have all been adopted as therapeutic strategies to improve vision in AMD.

  • Treatment of dry non‐vascular AMD: according to the Age‐Related Eye Disease Study trial, antioxidant vitamins such as Vitamins C, E, A and lutein plus zinc were suggested for patients with dry non‐vascular AMD (Age‐Related Eye Disease Study Research, 2001a, 2001b).

  • Treatment of wet neovascular AMD: Effective treatment for wet neovascular AMD includes intravitreous injection of anti‐VEGF therapies, photodynamic therapy (PDT) and supplementation with antioxidant vitamins and zinc. Anti‐VEGF therapies such as bevacizumab, ranibizumab or aflibercept are strongly recommended for patients with neovascularization and PTD is suggested as an alternative for patients who cannot receive intravitreal injection with anti‐VEGF (Bandello et al., 2017; Hernandez‐Zimbron et al., 2018; Su et al., 2018).

Bioactive lipids

Lipids and their metabolites are not only components of cellular membranes but also they act as signalling molecules and are thus known as ‘bioactive lipids’. Among the key activities exerted by bioactive lipids are angiogenesis, regulation of inflammation and maintenance of homeostasis. Bioactive lipids cover a large number and variety of compounds and the most commonly ones are those derived from polyunsaturated fatty acids (PUFAs).

PUFA‐derived metabolites

These metabolites are produced in a two‐step reaction sequence. The first step is carried out by the action of PLA2 enzyme which releases PUFAs such as linoleic acid (LA), arachidonic acid (AA) which is the most common, DHA and eicosapentanoic acid (EPA) from the cell membrane lipid layers. Those released PUFAs undergo the second step to be metabolized either via COX enzymes, cytochrome P450 (CYP) enzyme or lipoxygenases (LO) enzymes. There is much evidence that metabolites of the ω‐6 PUFA, such as AA, via the three major enzymic pathways produce pro‐inflammatory and pro‐angiogenic effects. These effects are mostly opposed by those of the metabolites from the ω‐3 PUFAs, DHA and EPA (Figures 3 and 5).

  • COX‐derived metabolites

Figure 3.

Figure 3

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(A) ω‐6 (arachidonic acid; AA)‐derived bioactive lipids or eicosanoids. Activation of PLA2 releases AA from the cell membrane phospholipids. AA is metabolized by COX to PGs, by CYP450 to EETs and by LO to HETEs (5, 12, 15‐HETEs), leukotrienes and lipoxins. (B) ω‐3‐derived bioactive lipids. PLA2 releases the ω‐3 polyunsaturated acids, DHA and EPA from the cell membrane phospholipids. DHA and EPA are converted by CYP450 to 19, 20‐EDP and 17, 18‐EEQ, by COX to PGE3, PGI3, TXA3 and LTB5 and by lipoxygenases to lipoxins, resolvins, neuroprotectins and LTB5.

Figure 5.

Figure 5

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The pro‐angiogenic versus anti‐angiogenic effect of lipoxygenase and CYP450 metabolites. Metabolites of 12/15‐LO from AA such as 12‐ or 15‐HETE are primarily pro‐angiogenic while the metabolites from DHA and EPA such as lipoxins, resolvins and neuroprotectins are primarily anti‐angiogenic. Similarly, the metabolites formed by CYP450 from AA such as 11‐ and 12‐EET elicit pro‐angiogenic effects while its products from EPA or DHA, such as 17, 18‐EEQ or 19, 20‐EDP respectively, induce anti‐angiogenic effects.

There are two main COX isoforms, COX‐1 and COX‐2. Both convert AA into PGH2, which is then converted by appropriate synthases, into PGs and TXs which are collectively known as prostanoids (Sales et al., 2008). The most important prostanoids are PGE2, PGF2α, PGD2, PGI2 and TxA2 (Figure 3). PGE2 is a key proinflammatory PG which has anti‐apoptotic properties with important functions in the immunity and cancer development. PGF2α is an autocrine growth factor related to endometrial carcinoma (Sales et al., 2008; Woodward et al., 2011). TxA2 (synthesized by platelets) and PGI2 (synthesized by endothelium) (Catella‐Lawson et al., 1999) have important roles in both the physiology and pathology of blood vessels. TxA2 causes platelet aggregation and vasoconstriction, while PGI2 has opposing effects (Caughey et al., 2001a, 2001b; Meyer‐Kirchrath et al., 2004). Interestingly, PG signalling is involved in chronic inflammatory diseases, for instance, asthma or Crohn's disease. This may happen via their ability to enhance the release of proinflammatory cytokines, their ability to activate proinflammatory T cells or macrophages (Claar et al., 2015; Wallace, 2018). In addition to COX‐derived proinflammatory metabolites from AA, COX converts ω‐3 PUFA, DHA and EPA to other anti‐inflammatory metabolites such as PGE3, and PGI3.

  • Cytochrome P450‐derived metabolites

In the linear metabolism of AA, cytochrome P450s (CYP450) metabolize this PUFA to oxidized eicosanoids such as epoxyeicosatrienoic acids (EETs; 5,6‐EET, 8,9‐EET, 11,12‐EET and 14,15‐EET), dihydroxyeicosatrienoic acids (DHETs) and 20‐hydroxyeicosatetraenoic acid (20‐HETE). EETs are further metabolized by soluble epoxide hydrolase enzyme (sEH) into DHETs (Huang et al., 2016). In addition to AA, CYP450 also metabolizes docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) into epoxydocosapentaenoic acids (EDPs) and epoxyeicosatetraenoic acids (EEQs) respectively. CYP450‐derived eicosanoids are formed in a tissue and cell‐specific way with many biological functions. Interestingly, EETs and 20‐HETE have opposing actions within the vasculature. The vascular role of CYP‐derived metabolites has been initially linked to regulation of vascular tone via endothelium‐derived hyperpolarizing factor (Campbell et al., 1996). EETs have powerful vasodilatory effect while 20‐HETE is a strong vasoconstrictor. Both EDPs and EEQs exhibit potent vasodilatory and cardioprotective effects (Konkel and Schunck, 2011).

CYP450‐derived eicosanoids have been also linked to angiogenesis. However, the role of the various CYP450 isoforms and their metabolites is complicated by evidence that suggests metabolites of CYP450 from AA elicit pro‐angiogenic effects, while its metabolites from DHA and EPA are anti‐angiogenic (Yanai et al., 2014).

  • Lipoxygenase‐derived metabolites

The second arm of linear metabolism of PUFAs is carried out by lipoxygenases (LOs), which are non‐haem iron‐containing lipid peroxidizing enzymes which catalyse dioxygenation of PUFAs, forming a wide variety of bioactive lipids (Kuhn et al., 2015). The phylogenetic distribution of LOs demonstrates their wide distribution across both the plant and animal kingdoms. The human genome contains one functional LO gene located on chromosome 10 (ALOX5) and five genes located on chromosome 17 (ALOX15, ALOX15B, ALOX12, ALOX12B, ALOXE3), which encode for six different LO isoforms (Funk et al., 2002). The ALOX15 gene encodes for 12/15‐LO, the ALOX15B gene encodes for 15‐LO2, the ALOX12 gene encodes for the platelet‐type 12‐LO, the ALOX12B gene encodes for a 12R‐LO enzyme, the ALOXE3 gene encodes for two epidermal LO isoforms and finally, the ALOX5 gene encodes for 5‐LO enzyme. The corresponding mouse genes were located on chromosomes 6 (Alox5) and 11 (other Lo isoforms). These genes encode for slightly different LO enzymes in mice (Kinzig et al., 1999; Meruvu et al., 2005; Yu et al., 2006). Mammalian LO isoforms have diverse biological functions. Different LO isoforms are involved in the synthesis of RBCs, differentiation of epidermis and atherosclerosis, via their ability to oxidize esterified membrane lipids and thus to modify their structural and functional propertties (Chen et al., 1994; Sun and Funk, 1996; Kinzig et al., 1999; Capra et al., 2013). LOs affect different cellular functions via their ability to modify the cellular redox status. LOs form lipid peroxides which change the intracellular redox balance and are implicated in the induction of oxidative stress (Othman et al., 2013; Elmasry et al., 2018).

A number of LO derived‐bioactive lipids and some LO isoforms have been associated with the pathogenesis of multiple metabolic disorders including diabetes both type 1 and type 2. Interestingly, 12‐hydroxyeicosatrienoic acids (12‐HETE) derived from either ALOX15 or ALOX12 and ALOX5 derived‐leukotriene B4 were elevated in diabetic patients (Issan et al., 2013). Particularly for ALOX15, there is good evidence to connect the enzyme to the pathogenesis of diabetes (Bleich et al., 1998, 1999; Laybutt et al., 2002; Chen et al., 2005a; Nunemaker et al., 2008; Sears et al., 2009). Expression of ALOX15 was significantly increased in both cell culture and animal models of diabetes. This may be related in part to LO‐induced oxidative stress (Dobrian et al., 2011; Zhang et al., 2013). In general, 12/15‐LO and 5‐LO convert AA to pro‐inflammatory and pro‐angiogenic metabolites such as 12‐ and 15‐HETEs and leukotrienes (Lee et al., 2004; Al‐Shabrawey et al., 2011; Faulkner et al., 2015; Ibrahim et al., 2017).

Linoleic acid (LA), arachidonic acid (AA), EPA and DHA are possible substrates for ALOX15. The enzyme binding site for the fatty acid substrates is a hydrophobic pocket close to the non‐haem iron into which the substrate slides with its methyl end in front (Kuhn et al., 1986; Rickert and Klinman, 1999). Phospholipids (Schewe et al., 1975) and cholesterol esters (Belkner et al., 1991) containing polyunsaturated fatty acids are also possible substrates to ALOX15. The ability of ALOX15 to oxygenate phospholipids was not expected, because the phospholipid molecule is too big to fit in the binding site of ALOX15. This can only be explained if the enzyme shows a high degree of structural flexibility, allowing the active site to rearrange, in order to facilitate phospholipid binding. Moreover, membrane lipids, ester lipids of low‐density lipoproteins and lipoproteins were reported to be additional substrates for ALOX15 (Kuhn et al., 1990; Belkner et al., 1993). This activity of ALOX15 suggested a mechanism for explaining how the bio‐membranes are reformed during the process of maturational degradation of cellular organelles (van Leyen et al., 1998). When LA is the ALOX15 substrate, the main products of the enzymic reaction are 13‐HODE or 9‐HODE. When arachidonic acid is the substrate, ALOX15 produces 15‐HETE or 12‐HETE. These different products are due to the dual positional specificity of ALOX15. Furthermore, 12/15‐LO metabolizes EPA and DHA to lipoxins and resolvins that exhibt anti‐inflammatory and anti‐angiogenic effects (Jin et al., 2009).

Bioactive lipids and retinopathies

Bioactive lipids such as PUFAs and their derivatives were reported to have a role in the pathogenesis of retinopathies including ROP, AMD and DR.

A significant reduction of retinal angiogenesis in ROP has been reported by dietary uptake of ω‐3 PUFAs which was associated with reduced retinal‐ER stress (Fu et al., 2015). Additionally, 12/15‐LO (ALOX15) and CYP are involved in pathological RNV in the OIR and hence, inhibition of 12/15‐LO or CYP significantly reduced RNV in an OIR model (Al‐Shabrawey et al., 2011; Capozzi et al., 2014). Additional results were obtained with bovine retinal endothelial cells, highlighting the role of CYP450 and its EET derivatives in retinal angiogenesis (Michaelis et al., 2008). CYP450‐derived EETs are further metabolized by sEH. Interestingly, mice lacking sEH showed defective angiogenesis via dysregulating Notch signalling, particularly in Müller cells (Hu et al., 2014).

In early stages of AMD, lipid‐containing deposits, called drusen, appear in Bruch's membrane underlying the RPE, suggesting a role of lipids in the pathogenesis of AMD (Shen et al., 2016). Earlier studies demonstrated that ω‐3 PUFAs, such as EPA, reduced CNV associated with AMD. Additionally, ω‐3 PUFAs such as EPA and DHA protected photoreceptors against oxidative stress (Sala et al., 2010). These studies highlight the protective role of ω‐3 PUFAs against AMD development and other pathological RNV as well (Connor et al., 2007; Koto et al., 2007). The protective effect was suggested to be related to 5‐LO‐dependent oxidation of DHA to 4‐hydroxy‐decosahexaenoic acid which inhibits endothelial proliferation and angiogenesis in a PPARγ‐dependent mechanism (Sapieha et al., 2011). Interestingly, in patients with wet‐AMD, a combined therapy of anti‐VEGF and ω‐3 PUFAs supplementation was associated with a greater reduction of VEGF levels in the vitreous, than with anti‐VEGF alone (Rezende et al., 2014). Furthermore, eyes derived from AMD donors had a lower level of very long chain PUFAs than those from normal donors, supporting the notion of the protective effect of PUFAs in AMD (Gorusupudi et al., 2016). On the other hand, oxidized phospholipids were reported to be increased in the eyes of AMD patients and to induce CNV in mice (Suzuki et al., 2007). Secondly, the sphingolipids, including ceramide (Cer), sphingosine (Sph) or sphingosine‐1‐phosphate (S1P) have been implicated in AMD, as well. Although S1P and Cer‐1‐phosphate appear to have a protective effect on photoreceptors and are involved in their differentiation and development (Miranda et al., 2009; Miranda et al., 2011), others showed that S1P can induce angiogenesis in either the choroid or the retina (Caballero et al., 2009; Xie et al., 2009). Lastly, accumulated cholesterol in retinal endothelial cells, macrophages and RPE cells is involved in the pathogenesis of AMD (Omarova et al., 2012; Saadane et al., 2014).

In DR, diabetes induces specific changes in retinal lipid metabolism. Diets rich in beneficial lipids, such as DHA or EPA, have been suggested as an alternative therapeutic strategy to prevent DR (Connor et al., 2007; Tikhonenko et al., 2010). DHA expresses anti‐inflammatory effects and it protected against pathological angiogenesis of the retina (Chen et al., 2005b; Connor et al., 2007). On the contrary, 5‐LO (ALOX5) and 12/15‐LO (ALOX15) both may have a role in the pathogenesis of DR. However, the findings suggested a differential role of the two enzymes. Retinas of diabetic 5‐Lo −/− mice and not 12/15‐Lo −/− showed less degeneration of retinal capillaries after 9 months of diabetes while retinas of both diabetic 5‐Lo −/− and 12/15‐Lo −/− showed less leucocyte adhesion at 3 months (Gubitosi‐Klug et al., 2008). Moreover, 12/15‐LO‐derived bioactive lipids were significantly increased in the vitreous of patients with proliferative DR (Al‐Shabrawey et al., 2011) and in epiretinal membranes as well (Augustin et al., 1997).

ALOX15 has been associated with regulation of endothelial permeability which contributes to the pathogenesis of vascular diseases including DR. 15S‐HETE, the major ALOX15 metabolite of AA in humans, increased endothelial barrier permeability via phosphorylation of zonula occludens‐1 and ‐2, which leads to disruption of the tight junctions causing a decrease in the integrity of the endothelial barrier and increasing the permeability (Kundumani‐Sridharan et al., 2013; Chattopadhyay et al., 2014; Ibrahim et al., 2015a). Moreover, ALOX15 is involved in disruption of endothelial tight junctions (Kundumani‐Sridharan et al., 2013; Chattopadhyay et al., 2015). We have reported that ALOX15 bioactive lipids induce retinal endothelial cell barrier dysfunction in retinal endothelial cells via NADPH‐oxidase dependent mechanisms, which include inhibition of protein tyrosine phosphatase and activation of the VEGF‐receptor 2 signalling pathway (Othman et al., 2013). The involvement of NADPH oxidase in ALOX15‐induced retinal endothelial barrier dysfunction highlighted the importance of the cellular redox state for the integrity of the endothelial barrier. Other reports suggested for the first time a role of ALOX15 in the process of autophagy, as cells lacking ALOX15 showed dysfunctional autophagy (Morgan et al., 2015).

Several studies by us and others have elaborated a possible role of ALOX15 in the pathogenesis of inflammation in DR and other diseases (Othman et al., 2013; Radmark et al., 2015; Ibrahim et al., 2015a ; Elmasry et al., 2018). Of note, activation of inflammatory signalling has been linked to the development of pathological RNV. The effect of ALOX15 during inflammation depends to a great extent on the substrate, as its products can exhibit both proinflammatory or anti‐inflammatory properties. For instance, with AA/LA as substrates, the main oxygenation products of ALOX15 (15‐HETE, 12‐HETE, 13‐HODE) exhibit pro‐inflammatory activities in various inflammation models (Kuhn, 1996). Reports suggested that the pro‐inflammatory properties of ALOX15 may be in part through affecting the cellular redox state and induction of oxidative stress (Kundumani‐Sridharan et al., 2013; Othman et al., 2013; Chattopadhyay et al., 2015; Ibrahim et al., 2015a; Elmasry et al., 2018). On the other hand, ALOX15 showed anti‐inflammatory properties when the substrates are either DHA or EPA via synthesis of pro‐resolving bioactive lipids that act to resolve inflammation (Sala et al., 2010; Serhan et al., 2015a). During the active process of resolution of inflammation, the pro‐inflammatory mediators are down‐regulated whereas the anti‐inflammatory mediators are up‐regulated. These anti‐inflammatory and anti‐angiogenic products of ALOX15 include lipoxins (Ryan and Godson, 2010), resolvins (Spite et al., 2014), protectins and maresins (Serhan et al., 2015b). These mediators induce some anti‐inflammatory processes including inhibition of leucocyte migration (Freire and Van Dyke, 2013), stabilization of vascular permeability (Ereso et al., 2009), apoptosis of proinflammatory neutrophils (El Kebir and Filep, 2013) and polarization of macrophages (Ohira et al., 2010). In addition to their resolving effects on innate immunity, lipoxins and recolvins elicit anti‐angiogenic effects in the eye through regulating VEGF and VEGFR2 expression and signalling (Wolfe, 1991; Jin et al., 2009).

To study the biological effects of 12/15‐LO metabolites, several pharmacological inhibitors have been developed. However, many of the 12/15‐LO inhibitors used (NDGA, CDC, baicalein) did not show a clear isoform specificity (Rai et al., 2010; Kenyon et al., 2011). Moreover, these inhibitors display a species‐specificity which means some inhibitors that effectively inhibit human ALOX15 may not inhibit orthologous enzymes of other species. In addition, those inhibitors had off‐target effects. 12/15‐LO inhibitors have anti‐oxidative properties and they affect the cellular redox homeostasis. It is difficult to distinguish which of the two functions (LO inhibition or redox homeostasis) is the main cause for the detected biological result (Goswami, 2013; Kim et al., 2013). Therefore, results acquired with these inhibitors must be interpreted with caution. To avoid these problems, the inhibitor studies should always be confirmed by another method, for example, the use of the 12/15‐Lo siRNA or 12/15‐Lo −/− mice.

We have been studying the potential role of 12/15‐LO metabolites in the pathogenesis of retinal vascular dysfunction in ischaemic retinopathies for several years. Our human studies showed significant increases in the vitreous levels of 12‐ and 15‐HETEs in patients with proliferative DR. Furthermore, we reported up‐regulation of retinal 12/15‐LO expression and activity in experimental models of DR and OIR (Al‐Shabrawey et al., 2011). Pharmacological inhibition and genetic deletion of 12/15‐LO significantly reduced RNV in OIR (Al‐Shabrawey et al., 2011) and preserved barrier function in DR (Ibrahim et al., 2015a). Recently, we elaborated the underlying cellular and molecular mechanisms of the pro‐inflammatory and pro‐angiogenic effects of 12/15‐LO in ischaemic retinopathies. We found that increased 12/15‐LO in OIR and DR was localized mainly in retinal vessels (Al‐Shabrawey et al., 2011). This was supported by in vitro studies in which the endothelial, rather than the leucocytic, 12/15‐LO was involved in hyperglycaemia‐induced dysfunction of retinal endothelial cell (RECs) (Ibrahim et al., 2017). Treatment of Müller cells with HETEs, metabolites of 12/15‐LO, up‐regulated the proangiogenic and proinflammatory factors VEGF, IL6 and TNFα but suppressed the expression of the angiostatic and neurotrophic factor PEDF (Al‐Shabrawey et al., 2011; Ibrahim et al., 2015b). On the other hand, they induced ER stress, NADPH‐oxidase‐derived ROS and adhesion molecules in RECs (Ibrahim et al., 2015a; Elmasry et al., 2018). Interestingly, while HETEs did not change the levels of VEGF expression in RECs, they increased the levels of phosphorylated VEGFR2 and inhibited the protein tyrosine phosphatase (PTP) (Othman et al., 2013; Elmasry et al., 2018). Taken together, our data suggest that activation of endothelial 12/15‐LO during ischaemic retinopathies induces two parallel paracrine and autocrine proangiogenic pathways through activation of Müller and RECs respectively. Endothelial‐derived HETEs up‐regulate VEGF and suppress PEDF in Müller cells. On the other hand, they activate VEGFR2 in REC via ER stress/NADPH oxidase‐dependent pathways that involve the dysregulation of PTP to release its inhibitory effect on VEGFR2. These effects are summarized in Figure 4.

Figure 4.

Figure 4

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Role of 12/15‐lipoxygenase in retinal neovascularization. Our studies demonstrated increased expression and activity of 12/15‐lipoxygenase in retinal endothelial cells of experimental models of diabetes and oxygen‐induced retinopathy. Endothelial‐derived metabolites of 12/15‐lipoxygenase (12‐ and 15‐HETEs) induce retinal neovascularization via paracrine and autocrine loops that activates Müller and endothelial cells respectively. Activation of Müller cells by HETEs (products of endothelial 12/15‐LO) up‐regulates VEGF and inflammatory cytokines and suppresses the angiostatic factor PEDF. However, activation of retinal endothelial cells by HETEs causes ER stress and activation of NADPH oxidase that lead to activation of VEGFR2 without affecting the endothelial levels of VEGF.

COX‐derived eicosanoids play a regulatory role in VEGF signalling and angiogenesis. While AA metabolites of COX elicit pro‐angiogenic effects, the underlying mechanism by which ω‐3 PUFAs regulate angiogenesis is via decreased synthesis of pro‐angiogenic ω‐6 prostanoids coupled with increased levels of less active ω‐3 prostanoids such as PGE3, PGI3, TXA3 and LTB5 (Figure 3B). Selective inhibition of COX2 has been reported to reduce inflammation and pathological RNV in experimental models of DR, CNV and OIR (Wilkinson‐Berka et al., 2003; Suzuki et al., 2012; Zhang et al., 2016).

Conclusion

Although VEGF plays a central role in the development of DR, AMD and ROP, anti‐VEGF therapies do not totally suppress the pathological RNV. PUFA‐derived metabolites regulate the production of VEGF, oxidative stress and inflammatory cytokines, as well as being involved in the pathophysiology of these diseases. The development of LC–MS assays allows detailed retinal lipidomic analysis in retinal diseases to be a reality. Furthermore, the availability of COX, LO, CYP enzyme inhibitors and transgenic mice permits the study of the functions and dysfunctions of PUFA signalling in proliferative retinopathies. By taking the advantage of these invaluable tools, we need to deepen our understanding of the role of PUFA‐derived metabolites in the pathophysiology of these vision threatening diseases and to clinically evaluate the possible therapeutic use of COX, LO and CYP enzyme inhibitors in these conditions. As shown in Figure 5, the metabolites of these three enzymatic pathways may induce retinal angiogenic and angiostatic effects, depending on the PUFA substrate. If the substrate is AA, most of the metabolites will be pro‐angiogenic, whereas if the substrate is DHA or EPA, the anti‐angiogenic effects will be more dominant. This information is the foundation of dietary supplementation of ω‐3 PUFA as a potential treatment of ischaemic retinopathies to halt the progression of RNV.

Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al., 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 (Alexander et al., 2017a, 2017b).

Conflict of interest

The authors declare no conflicts of interest.

Acknowledgements

This work has been supported by the National Eye Institute grant R01EY023315 (MA) and the American Heart Association grant 18CDA34080403 (ASI).

Elmasry, K. , Ibrahim, A. S. , Abdulmoneim, S. , and Al‐Shabrawey, M. (2019) Bioactive lipids and pathological retinal angiogenesis. British Journal of Pharmacology, 176: 93–109. 10.1111/bph.14507.

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