Ординатура / Офтальмология / Английские материалы / Retinal and Choroidal Angiogenesis_Penn_2008

Figure 12-5. Schematic of the role of ADO in vasculogenesis in neonatal dog retina and vasoobliteration and vasoproliferation in the canine model of oxygen-induced retinopathy. Normal vasculogenesis: ADPase-positive angioblasts change from a round morphology to spindle-shaped morphology and express A2A receptors as they migrate through cell-free spaces formed by inner Müller cell processes. They organize into blood vessels in the anterior portion of these spaces. The inner Müller cell processes surrounding these spaces have high 5’N activity (black), which generates adenosine (red dots). Vaso-obliteration: Exposure to hyperoxia causes a significant decrease in 5’N activity and adenosine, severe vasoconstriction, and blood vessel degeneration while A2A levels do not change. Vasoproliferation: Following return to room air, angiogenesis occurs within retina and preretinal neovascularization forms. 5’N activity is greatly elevated in the inner Müller cell processes (black), resulting in high levels of adenosine (red) in inner retina. Astrogliosis occurs in inner retina during the vasoproliferative stage, and the cell-free spaces are filled with astrocytes (green cells). From Lutty and McLeod, Prog Ret Eye Res 2003;22:95-111.85

One of the A2 receptors may be a therapeutic target for angiogenesis in OIR. There may be a difference between species in terms of which A2 receptor is associated with neovascularization in the retina, based on comparisons of our studies and those of Maria Grant’s laboratory.1,58 The difference may not be important, however, because both A2 receptors act through Gs-proteins, resulting in the same stimulatory effect. Also, there may be redundancy in the system. For example, Morrison et al. recently demonstrated that, in A2A knockout mice, coronary function normally attributed to A2A was conferred when A2B agonists were administered.79

Although the A2 receptors are logical therapeutic targets for stopping retinal angiogenesis, therapy targeting A2 receptors may be dangerous unless delivered specifically to eye. Systemic administration of A2 antagonists

could have serious negative effects on cardiac and central nervous system development and function.4,23,80 In any case, the duration of therapy and must

be limited so as not to inhibit the neuromodulatory role of A2A in more mature retinas.

Future therapies could include local delivery of A2 antagonists or 5’ nucleotidase inhibitors, perhaps by degradable polymers, to retina from vitreous. Unfortunately to date, the only potent inhibitor for 5’N, α,β- methylene adenosine 5’-diphosphate,59 is not tolerated well in the eye (unpublished data). Potent A2 antagonists have been developed recently that have greater water solubility than the original agents.3 It may also be possible to target the A2 receptors with antisense probes as was done successfully with VEGF. Grant and associates have evaluated a unique approach to targeting adenosine therapeutically: the use of a ribozyme. They have developed a ribozyme that degrades the mRNA for the A2B receptor and successfully inhibited angiogenesis in the mouse model of OIR by injecting it into vitreous.81 These potential therapies may have the positive effect of preventing adenosine action and, therefore, indirectly affecting production of VEGF as well.

ACKNOWLEDGMENTS

The author acknowledges his collaborators Makoto Taomoto, M.D., and Carol Merges, M.A.S., who contributed substantially to the studies discussed in this manuscript, Andrew Newby, M.D., for his generosity in providing the antibody against adenosine, and Maria Grant, M.D., for helpful discussions. This work was supported by NIH grants EY 01765 (Wilmer Institute) and EY09357 (G. A. L.), the ROPARD Foundation (G. A. L.), Research to Prevent Blindness (Wilmer), and the Brownstein Foundation. G. A. L. is an

American Heart Association Established Investigator and the recipient of a Research to Prevent Blindness Lew Wasserman Merit Award.

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Chapter 13

THE REGULATION OF RETINAL ANGIOGENESIS BY CYCLOOXYGENASE AND THE PROSTANOIDS

Gary W. McCollum and John S. Penn

Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee

1.INTRODUCTION

Prostaglandins (PGs), prostacyclins (PGIs), and thromboxanes (TXs), collectively referred to as the prostanoids, are lipid-derived autocrine/paracrine signaling molecules that are involved in a wide range of physiological and pathophysiological processes.1 Since their discovery, the prostanoid literature has burgeoned into a wealth of experimental data suggesting complicated and often contradictory roles in, but by no means limited to: the immune response, inflammatory response, female reproductive biology, wound healing, arthritis, asthma, atherosclerosis, gastric ulcers, and cancer.1 Recent studies suggest roles for prostanoids in the context of ocular angiogenesis, and bear relevance to the pathological neovascular component of several potentially blinding conditions such as macular degeneration, diabetic retinopathy, retinal vein

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© Springer Science+Business Media B.V. 2008

occlusion and retinopathy of prematurity.2-5 Herein, these studies and their findings will be discussed.

2.PROSTANOID SYNTHESIS

The discovery of the prostanoids resulted from the findings of two landmark studies conducted in the 1930s: the identification and characterization of the essential fatty acids, and isolation of a biological activity from human seminal fluid that would contract smooth muscle preparations.6-8 The prostaglandins E (PGE), F (PGF), and D (PGD) were the first to be characterized followed by the thromboxanes, prostacyclin and the leukotrienes. Subsequent studies demonstrated that essential fatty acids are converted to prostanoids by oxygenation pathways.9 Prostanoids are further classified into either series-1, -2 or -3 depending on which of three precursor essential fatty acids serves as the substrate for the oxygenation reactions (i.e., PGE1, PGE2, and PGE3). Series-1 and -3 are synthesized from γ-homolinolenic acid and eicosapentaenoic acid (20:5ω-3), respectively. Series-2 prostanoids are synthesized from arachidonic acid, the most abundant prostanoid precursor in humans.9,10 The initial step of series-2 prostanoid biosynthesis is arachidonic acid release from membrane phospholipids in a reaction catalyzed by phospholipase A2 (PLA2). There are at least 19 groups of PLA2s that are generally classified as cytosolic (cPLA2), secretory (sPLA2) or calcium-independent (iPLA2). PLA2 is activated in response to numerous stimuli including ischemia, oxidative stress, and cell signaling molecules.11 A cyclooxygenase (COX) enzyme catalyzes the reaction between two molecules of O2 and arachidonic acid. The catalytic domain of COX has two distinct active sites: the COX active site catalyzes the formation of endoperoxide and hydroperoxyl functionalities to produce prostaglandin G2 (PGG2), and the peroxidase active site catalyzes the reduction of the hydroperoxyl group to a hydroxyl group to form PGH2. Cell-specific synthases catalyze isomerization, oxidation, and reduction of PGH2 to yield the prostanoids (see Figure 1).