Adenosine in Retinal Vasculogenesis and Angiogenesis in Oxygen-Induced Retinopathy
Adenosine is a ubiquitous molecule produced predominantly by catabolism of adenosine triphosphate. Levels of this nucleoside increase dramatically with ischemia and elevated tissue activity. Adenosine induces angiogenesis in tumors and wound healing and upregulates VEGF production in several cell types, including endothelial cells. The source of adenosine in most tissues appears to be the ectoenzyme 5’ nucleotidase, which is hypoxia inducible. 5’ nucleotidase expression is prominent during retinal vascular development in the innermost processes of Muller cells, and levels of its product, adenosine, are high in inner retina during retinal vascular development in postnatal dog. One of the adenosine receptors, A2A, is present on angioblasts and on endothelial cells of formed blood vessels during canine retinal vascular development. These observations suggest that adenosine is important in retinal vascular development.
Oxygen-induced retinopathy (OIR) is a model for human retinopathy of prematurity (ROP). OIR is induced by exposure of the developing retina to high oxygen. Vascular development is halted, and over 60% of the retinal vasculature is lost during this stage, which is called vaso-obliteration. Expression of 5’ nucleotidase is dramatically reduced during vaso-obliteration, resulting in a sharp decline in adenosine. When animals are returned to room air, the retina is hypoxic because of the lack of blood vessels and increased oxygen consumption due to neuronal development. At this time, the vasoproliferative stage of OIR begins, and 5’ nucleotidase activity and adenosine levels become elevated well beyond normal. A2A-positive endothelial cell proliferation is also elevated compared to control animals. Florid preretinal neovascularization occurs and is characterized by high levels of adenosine and A2A receptors. Therefore, adenosine and its A2A receptor appear to be important in canine OIR. This has also been demonstrated in the mouse model of OIR. Systemically administered antagonists of the adenosine A2B receptor significantly reduced retinal neovascularization in mice,1 as did cleavage of A2B by a ribozyme.2 These studies suggest that adenosine and its receptors are important in retinal vascular development and may be a therapeutic target in OIR.
KeywordsMigration Ischemia Adenosine Retina Succinate
R. P. Mino, P. E. Spoerri, S. Caballero, D. Player, L. Belardinelli, I. Biaggioni, and M. B. Grant, Adenosine receptor antagonists and retinal neovascularization in vivo, Invest. Ophthalmol. Vis. Sci.
(13), 3320-3324 (2001).PubMedGoogle Scholar
A. Afzal, L. Shaw, S. Caballero, P. Spoerri, A. Lewin, D. Zeng, L. Belardinelli, and M. B. Grant, Reduction in preretinal neovascularization by ribozymes that cleave the A2b adenosine receptor mRNA, Circ. Res.
, 500-506 (2003).PubMedCrossRefGoogle Scholar
J. Linden, Molecular approach to adenosine receptors: receptor-mediated mechanisms of tissue protection, Annu. Rev. Pharmacol. Toxicol.
, 775-787 (2001).PubMedCrossRefGoogle Scholar
S. A. Rivkees, Z. Zhao, G. Porter, and C. Turner, Influences of adenosine on the fetus and newborn, Mol. Genet. Metab.
(1-2), 160-171 (2001).PubMedCrossRefGoogle Scholar
G. Schopf, H. Rumpold, and M. M. Muller, Alterations of purine salvage pathways during differentiation of rat heart myoblasts toward myocytes, Biochimica et Biophysica Acta
, 319-325 (1986).PubMedGoogle Scholar
N. Braun, C. Lenz, F. Gillardon, M. Zimmerman, and H. Zimmerman, Focal cerebral ischemia enhances glial expression of ecto-5’-nucleotidase, Brain Res.
, 213-226 (1997).PubMedCrossRefGoogle Scholar
M. Kitakaze, M. Hori, and T. Kamada, Role of adenosine and its interaction with alpha adrenoceptor activity in ischaemic and reperfusion injury of the myocardium, Cardiovascular Res.
, 18-27 (1993).Google Scholar
K. Synnestvedt, G. T. Furuta, K. M. Comerford, N. Louis, J. Karhausen, H. K. Eltzschig, K. R. Hansen, L. F. Thompson, and S. P. Colgan, Ecto-5’-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia, J. Clin. Invest.
(7), 993-1002 (2002).PubMedCrossRefGoogle Scholar
M. Freissmuth, W. Schutz, and M. E. Linder, Interactions of the bovine brain A1-adenosine receptor with recombinant G protein a-subunits. Selectivity for rGioa - 3
, J. Biol. Chem.
, 17778-17783 (1991).PubMedGoogle Scholar
C. Blazynski, Adenosine A1
receptor-mediated inhibition of adenylate cyclase in rabbit retina, J. Neuroscience
, 2522-2528 (1987).Google Scholar
W. Abebe and S. J. Mustafa, A1
adenosine receptor mediated Ins(1,4,5)P3 generation in allergic rabbit airway smooth muscle, Am. J. Physiol.
, L990-L997 (1998).Google Scholar
B. T. Liang, Direct preconditioning of cardiac ventricular myocytes via adensoine A1
channel, Am. J.Physiol.
, H1769-H1777 (1996).PubMedGoogle Scholar
R. B. Marala and S. J. Mustafa, Immunological characterization of adenosine A2a
receptors in human and porcine cardiovascular tissue, J. Pharmacol. Exp. Ther.
, 1051-1057 (1998).PubMedGoogle Scholar
V. Stefanovic, P. Vlahovic, V. Savic, and R. Ardaillou, Adenosine stimulates 5’-nucleotidase activity in rat mesangial cells via A2
receptor, FEBS Lett.
, 96-100 (1993).PubMedCrossRefGoogle Scholar
S. N. Li and P. T. Wong, The adenosine receptor agonist, APNEA, increases Ca+ +
influx into rat cortical synaptosomes through N-type channels associated with A2a
receptors, Neurochem. Res.
, 457-459 (2000).PubMedCrossRefGoogle Scholar
T. M. Palmer, T. W. Gettys, and G. L. Stiles, Differentail interaction with and regulation of multiple G-proteins by the rat A3 adenossne receptor, J. Biol. Chem.
, 16895-16902 (1995).PubMedCrossRefGoogle Scholar
M. P. Abbracchio, R. Brambilla, S. Ceruti, H. O. Kim, D. K. von Lubitz, and K. A. Jacobsen, G protein-dependent activation of phospholipase C by adensoine A3
receptors in rat brain, Mol. Pharmacol.
, 1038-1045 (1995).PubMedGoogle Scholar
Z. Zhao, C. E. Francis, and K. Ravid, An A3
-subtype receptor is highly expressed in rat smooth muscle cells: its role in attenuating adensoine-induced increase in camp, Microvasc. Res.
, 243-252 (1997).PubMedCrossRefGoogle Scholar
Z. Zhao, K. Makaritsis, C. E. Francis, H. Gavris, and K. Ravid, A role for the A3 adensoine receptor in determining tissue levels of cAMP and blood pressure: studies in knockout mice, Biochem. Biophys. Acta
, 280-290 (2000).PubMedGoogle Scholar
R. Berne, R. Knabb, S. W. Ely, and R. Rubio, Adenosine in the local regulation of blood flow: a brief overview, Federation Proc.
, 3136-3142 (1983).Google Scholar
J. W. Phillis, Adenosine in the control of cerebral circulation, Cerebrovascular and Brain Metabolism Reviews
, 26-54 (1989).PubMedGoogle Scholar
H. Winn, S. Morii, and R. Berne, The role of adenosine in autoregulation of cerebral blood flow, Annals Biomed. Engineering
, 321-328 (1985).CrossRefGoogle Scholar
R. Tabrizchi and S. Bedi, Pharmacology of adenosine receptors in the vasculature, Pharmacol. Ther.
(2), 133-147 (2001).PubMedCrossRefGoogle Scholar
H. A. Olanrewaju and S. J. Mustafa, Adenosine A(2A) and A(2B) receptors mediated nitric oxide production in coronary artery endothelial cells, Gen. Pharmacol.
(3), 171-177 (2000).PubMedGoogle Scholar
J. W. Dusseau and P. M. Hutchins, Hypoxia-induced angiogenesis in chick chorioallantoic membranes: a role for adenosine, Respir. Physiol.
, 33-44 (1988).PubMedCrossRefGoogle Scholar
C. J. Meininger, M. E. Schelling, and H. J. Granger, Adenosine and hypoxia stimulate proliferation and migration of endothelial cells, Am. J. Physiol.
, H554-H562 (1988).PubMedGoogle Scholar
E. Teuscher and V. Weidlich, Adenosine nucleotides, adenosine and adenine as angiogenesis factors, Biomed. Biochim. Acta.
, 493-495 (1985).PubMedGoogle Scholar
G. A. Lutty, M. K. Mathews, C. Merges, and D. S. McLeod, Adenosine stimulates canine retinal microvascular endothelial cell migration and tube formation, Curr. Eye Res.
(6), 594-607 (1998).PubMedGoogle Scholar
H. A. Olanrewaju, W. Qin, I. Feoktistov, J. L. Scemama, and S. J. Mustafa, Adenosine A(2A) and A(2B) receptors in cultured human and porcine coronary artery endothelial cells, Am. J. Physiol. Heart Circ. Physiol.
(2), H650-H656 (2000).PubMedGoogle Scholar
I. Feoktistov, A. E. Goldstein, S. Ryzhov, D. Zeng, L. Belardinelli, T. Voyno-Yasenetskaya, and I. Biaggioni, Differential expression of adenosine receptors in human endothelial cells: role of A2B receptors in angiogenic factor regulation, Circ. Res.
(5), 531-538 (2002).PubMedCrossRefGoogle Scholar
R. K. Dubey, D. G. Gillespie, and E. K. Jackson, A(2B) adenosine receptors stimulate growth of porcine and rat arterial endothelial cells, Hypertension
(2 Pt 2), 530-535 (2002).PubMedCrossRefGoogle Scholar
M. B. Grant, M. I. Davis, S. Caballero, I. Feoktistov, I. Biaggioni, and L. Belardinelli, Proliferation, migration, and ERK activation in human retinal endothelial cells through A(2B) adenosine receptor stimulation, Invest. Ophthalmol. Vis. Sci.
(9), 2068-2073 (2001).PubMedGoogle Scholar
A. Desai, C. Victor-Vega, S. Gadangi, M. C. Montesinos, C. C. Chu, and B. N. Cronstein, Adenosine A2A receptor stimulation increases angiogenesis by down-regulating production of the antiangiogenic matrix protein thrombospondin 1, Mol. Pharmacol.
(5), 1406-1413 (2005).PubMedCrossRefGoogle Scholar
G. W. Kreutzberg and S. T. Hussain, Cytochemical heterogeneity of the glial plasma membrane: 5’-nucleotidase in retinal Müller cells, J. Neurocytol.
, 53-64 (1982).PubMedCrossRefGoogle Scholar
N. Braun, P. Brendel, and H. Zimmerman, Distribution of 5’-nucleotidase in the developing mouse retina, Brain Res.
, 79-86 (1995).CrossRefGoogle Scholar
G. A. Lutty, C. Merges, and D. S. McLeod, 5’ nucleotidase and adenosine during retinal vasculogenesis and oxygen- induced retinopathy, Invest. Ophthalmol. Vis. Sci.
(1), 218-229 (2000).PubMedGoogle Scholar
C. Blazynski and M. T. Perez, Neuroregulatory functions of adenosine in the retina, Prog. Retinal Res.
, 293-332 (1992).CrossRefGoogle Scholar
K. M. Braas, M. A. Zarbin, and S. H. Snyder, Endogenous adenosine and adenosine receptors localized to ganglion cells of the retina, Proc. Natl. Acad. Sci., USA
, 3906-3910 (1987).PubMedCrossRefGoogle Scholar
C. Blazynski, J. L. Mosinger, and A. I. Cohen, Comparison of adenosine uptake and endogenous adenosine-containing cells in mammalian retina, Vis. Neurosci.
, 109-116 (1989).PubMedGoogle Scholar
P. Ostwald, S. S. Park, A. Y. Toledando, and S. Roth, Adenosine receptor blockade and nitric oxide synthase inhibition in the retina: Impact upon post-ischemic hyperemia and the electroretinogram, Vis. Res.
, 3453-3461 (1997).PubMedCrossRefGoogle Scholar
J. M. Gidday and T. S. Park, Adenosine-mediated autoregulation of retinal arteriolar tone in the piglet, Invest. Ophthalmol. Vis. Sci.
, 2713-2719 (1993).PubMedGoogle Scholar
J. M. Gidday and T. S. Park, Microcirculatory responses to adenosine in the newborn pig, Pediatr. Res.
, 620-627 (1993).PubMedCrossRefGoogle Scholar
S. Roth, S. S. Park, C. W. Sikorski, J. Osinski, R. Chan, and K. Loomis, Concentrations of adenosine and its metabolites in the rat retina/choroid during reperfusion after ischemia, Curr. Eye Res.
, 875-885 (1997).PubMedCrossRefGoogle Scholar
S. Roth, P. S. Rosenbaum, J. Osinski, S. S. Park, A. Y. Toledano, B. Li, and A. A. Moshfeghi, Ischemia induces significant changes in purine nucleoside concentration in the retina-choroid in rats, Exp. Eye Res.
, 771-779 (1997).PubMedCrossRefGoogle Scholar
A. K. Larsen and N. N. Osbourne, Involvement of adenosine in retinal ischemia. Studies on rat, Invest. Ophthalmol. Vis. Sci.
, 2603-2611 (1996).PubMedGoogle Scholar
B. Li, P. S. Rosenbaum, N. M. Jennings, K. A. Maxwell, and S. Roth, Differential roles of adenosine receptor subtypes in retinal ischemia-reperfusion injury in the rat, Exp. Eye Res.
, 9-17 (1999).PubMedCrossRefGoogle Scholar
B. Li and S. Roth, Retinal preconditioning in the rat: requirement for adenosine and repetitive induction, Invest. Ophthalmol. Vis. Sci.
, 1200-1216 (1999).PubMedGoogle Scholar
G. J. Ghiardi, J. M. Gidday, and S. Roth, The purine nucleoside adenosine in retinal ischemia-reperfusion injury, Vision Res.
, 2519-2535 (1999).PubMedCrossRefGoogle Scholar
S. Fischer, H. S. Sharma, G. F. Kaliczek, and W. Schaper, Expression of vascular permeability factor/vascular endothelial growth factor in pig cerebral microvascular endothelial cells and its upregulation by adenosine, Mol. Brain Res.
, 141-148 (1995).PubMedCrossRefGoogle Scholar
H. Takagi, G. L. King, G. S. Robinson, N. Ferrara, and L. P. Aiello, Adenosine mediates hypoxic induction of vascular endothelial growth factor in retinal pericytes and endothelial cells, Invest. Ophthalmol. Vis. Sci.
, 2165-2176 (1996).PubMedGoogle Scholar
H. Takagi, G. L. King, N. Ferrara, and L. P. Aiello, Hypoxia regulates vascular endothelial growth factor receptor KDR/Flk gene expression through adenosine A2 receptors in retinal capillary endothelial cells, Invest. Ophthalmol. Vis. Sci.
, 1311-1321 (1996).PubMedGoogle Scholar
M. B. Grant, R. W. Tarnuzzer, S. Cabalerro, M. J. Ozeck, M. I. Davis, P. E. Spoerri, I. Feoktistov, I. Biaggioni, J. C. Shryock, and L. Belardinelli, Adenosine receptor activation induces vascular endothelial growth factor in human endothelial cells, Circ. Res.
, 699-706 (1999).PubMedGoogle Scholar
R. W. Flower, D. S. McLeod, G. A. Lutty, B. Goldberg, and S. D. Wajer, Postnatal retinal vascular development of the puppy, Invest. Ophthal. Vis. Sci.
, 957-968 (1985).PubMedGoogle Scholar
D. S. McLeod, R. Brownstein, and G. A. Lutty, Vaso-obliteration in the canine model of oxygen-induced retinopathy, Invest. Ophthalmol. Vis. Sci.
, 300-311 (1996).PubMedGoogle Scholar
D. S. McLeod and G. A. Lutty, Menadione-dependent alpha glycerophosphate and succinate dehydrogenases in the developing canine retina, Curr. Eye Res.
, 819-826 (1995).PubMedCrossRefGoogle Scholar
D. S. McLeod, G. A. Lutty, S. D. Wajer, and R. W. Flower, Visualization of a developing vasculature, Microvasc. Res.
, 257-269 (1987).PubMedCrossRefGoogle Scholar
T. Chan-Ling, D. S. McLeod, S. Hughes, L. Baxter, Y. Chu, T. Hasegawa, and G. A. Lutty, Astrocyte-endothelial cell relationships during human retinal vascular development, Invest. Ophthalmol. Vis. Sci.
, 2020-2032 (2004).PubMedCrossRefGoogle Scholar
M. Taomoto, D. S. McLeod, C. Merges, and G. A. Lutty, Localization of adenosine A2a receptor in retinal development and oxygen-induced retinopathy, Invest. Ophthalmol. Vis. Sci.
(1), 230-243 (2000).PubMedGoogle Scholar
A. Van Waarde, M. E. Stromski, G. Thulin, K. M. Guadio, M. Kashgarian, R. G. Shulman, and N. J. Siegel, Protection of the kidney against ischemic injury by inhibition of 5’-nucleotidase, Am. J. Physiol.
, F298-F305 (1989).PubMedGoogle Scholar
G. A. Gole, Animal models of retinopathy of prematurity, in: Retinopathy of prematurity
, edited by W. A. Silverman and J. T. Flynn (Blackwell Scientific Publications, Boston, 1985) pp. 53-95.Google Scholar
X. Reynaud and C. K. Dorey, Extraretinal neovascularization induced by hypoxic episodes in the neonatal rat, Invest. Ophthalmol. Vis. Sci.
, 3169-3177 (1994).PubMedGoogle Scholar
J. S. Penn, B. L. Tolman, and M. M. Henry, Oxygen-induced retinopathy in the rat: relationship of retinal nonperfusion to subsequent neovascularization, Invest. Ophthalmol. Vis. Sci.
, 3429-3435 (1994).PubMedGoogle Scholar
D. S. McLeod, S. A. D’Anna, and G. A. Lutty, Clinical and histopathologic features of canine oxygen-induced proliferative retinopathy, Invest. Ophthalmol. Vis. Sci.
(10), 1918-1932 (1998).PubMedGoogle Scholar
L. E. H. Smith, E. Wesolowski, A. McLellan, S. K. Kostyk, R. D. D’Amato, R. Sullivan R, and P. A. D’Amore, Oxygen-induced retinopathy in the mouse, Invest. Ophthalmol. Vis. Sci.
(1), 101-111 (1994).PubMedGoogle Scholar
T. Chan-Ling, S. Tout, H. Holländer, and J. Stone, Vascular changes and their mechanisms in the feline model of retinopathy of prematurity, Invest. Ophthalmol. Vis. Sci.
(7), 2128-2147 (1992).PubMedGoogle Scholar
N. Ashton, B. Ward, and G. Serpell, Effect of oxygen on developing retinal vessels with particular reference to the problem of retrolental fibroplasias, Br. J. Ophthalmol.
, 397-428 (1954).PubMedCrossRefGoogle Scholar
T. Chan-Ling, B. Gock, and J. Stone, The effect of oxygen on vasoformative cell division. Evidence that ‘physiological hypoxia’ is the stimulus for normal retinal vasculogenesis, Invest. Ophthalmol. Vis. Sci.
, 1201-1214 (1995).PubMedGoogle Scholar
A. Patz, Oxygen studies in retrolental fibroplasia:IV clinical and experimental observations, Am. J. Ophthalmol.
, 291-307 (1954).PubMedGoogle Scholar
M. Kitakaze, M. Hori, S. Takashima, K. Iwai, H. Sato, M. Inoue, A. Kitabatake, and T. Kamada, Superoxide dismutase enhances ischemia- induced reactive hyperemic flow and adenosine release in dogs, Circ. Res.
, 558-566 (1992).PubMedGoogle Scholar
M. Kitakaze, M. Hori, T. Morioka, S. Takashima, T. Minamino, H. Sato, M. Inoue, and T. Kamada, Attenuation of ecto-5’-nucleotidase activity and adenosine release in activated human polymorphonuclear leukocytes, Circ. Res.
, 524-533 (1993).PubMedGoogle Scholar
Y. F. Chen, P. L. Li, and A. P. Zou, Oxidative stress enhances the production and actions of adenosine in the kidney, Am. J. Physiol. Regulatory Integrative Comp. Physiol.
, R1808-R1816 (2001).Google Scholar
D. S. McLeod, S. N. Crone, and G. A. Lutty, Vasoproliferation in the neonatal dog model of oxygen-induced retinopathy, Invest. Ophthalmol. Vis. Sci.
(7), 1322-1333 (1996).PubMedGoogle Scholar
S. E. Brooks, X. Gu, S. Samuel, D. M. Marcus, M. Bartoli, P. L. Huang, and R. B. Caldwell, Reduced severity of oxygen-induced retinopathy in eNOS-deficient mice, Invest. Ophthalmol. Vis. Sci.
, 222-228 (2001).PubMedGoogle Scholar
C. D. Lewis, S. M. Hourani, C. J. Long, and M. G. Collis, Characterization of adenosine receptors in the rat isolated aorta, Gen. Pharmac.
, 1381-1387 (1994).Google Scholar
S. M. Poucher, J. R. Keddie, R. Brooks, G. R. Shaw, and D. McKillup, Pharmacodynamics of ZM 241385, a potent A2a adenosine antagonist, after enteric administration in rat, cat and dog, J. Pharm. Pharmacol.
, 601-606 (1996).PubMedGoogle Scholar
L. Sobrevia, D. L. Yudilevich, and G. E. Mann, Activation of A2-purinoceptors by adenosine stimulates L-arginine transport (system y+) and nitric oxide synthesis in fetal human endothelial cells, J. Physiol.
, 135-140 (1997).PubMedGoogle Scholar
S. J. Mustafa and W. Abebe, Coronary vasodilation by adenosine-receptor subtypes and mechanism of action, Drug Development Res.
, 308-313 (1996).CrossRefGoogle Scholar
D. S. McLeod, M. Taomoto, J. Cao, Z. Zhu, L. Witte, and G. A. Lutty, Localization of VEGF receptor-2 (KDR/FLK-1) and effects of blocking it in oxygen-induced retinopathy, Invest. Ophthalmol. Vis. Sci.
, 474-482 (2002).PubMedGoogle Scholar
R. R. Morrison, M. A. Talukder, C. Ledent, and S. J. Mustafa, Cardiac effects of adenosine in A(2A) receptor knockout hearts: uncovering A(2B) receptors, Am. J. Physiol. Heart Circ. Physiol.
(2), H437-H444 (2002).PubMedGoogle Scholar
J. L. Moreau and G. Huber, Central adenosine A(2A) receptors: an overview, Brain Res. Brain Res. Rev.
, 65-82 (1999).PubMedCrossRefGoogle Scholar
A. Afzal, L. C. Shaw, S. Caballero, E. A. Ellis, and M. B. Grant, The development of hammerhead ribozymes that specifically cleave the A2B receptor mRNA, Invest. Ophthalmol. Vis. Sci.
, ARVO abstract #3711 (2002).Google Scholar
J. A. Forsythe, B. Jiang, N. V. Iyer, F. Agani, S. W. Leung, R. D. Koos, and G. L. Semenza, Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1, Mol. Cell. Biol.
, 4604-4613 (1996).PubMedGoogle Scholar
P. H. Maxwell and P. J. Ratcliffe, Oxygen sensors and angiogenesis, Seminars in Cell & Developmental Biology
(1), 29-37 (2002).CrossRefGoogle Scholar
C. Michiels, E. Minet, G. Michel, D. Mottet, J. Piret, and M. Raes, HIF-1 and AP-1 cooperate to increase gene expression in hypoxia: role of MAP kinases, IUBMB Life
, 49-53 (2001).PubMedCrossRefGoogle Scholar
G. A. Lutty and D. S. McLeod, Retinal vascular development and oxygen-induced retinopathy: a role for adenosine, Prog. Ret. Eye Res.
, 95-111 (2003).CrossRefGoogle Scholar
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