|Molecular Vision 2005;
Received 6 December 2004 | Accepted 2 March 2005 | Published 7 July 2005
Melanization and phagocytosis: Implications for age related macular degeneration
Sarangarajan,1 Shireesh P.
1Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Worcester, MA; 2Baxter IV systems, Murray Hill, NJ
Correspondence to: Shireesh P. Apte, 2313 Welch Place, Mansfield, TX, 76063; Phone: (817) 453-1898; email: email@example.com
Signaling pathways that upregulate melanization in the retinal pigment epithelium (RPE) may also be implicated in the downregulation of rod outer segment (ROS) phagocytosis by the RPE. Melanization activating pathways may also modulate oxygen consumption by the photoreceptors, apolipoprotein E4 levels, and the rate of photoisomerization events such that the net effect may be a reduction in drusen and/or lipofuscin accumulation. An increase in melanin at the apical microvilli of the RPE may shield ROS from light thereby contributing in part to the decrease in the rate of ROS phagocytosis. This decrease in ROS phagocytosis by the RPE may serve to maintain a balance between ingestion and degradation/recycling thereby avoiding an increase to its already substantial metabolic load. Several experimental drugs for age related macular degeneration (ARMD) coincidentally are also capable of decreasing the rate of ROS phagocytosis. This review attempts to identify the signaling pathways that may link the upregulation of melanization to the downregulation of ROS phagocytosis. Phagocytic pathways that are modulated by melanization need to be studied in isolation to determine what role, if any, they possess in ameliorating the onset and progression of ARMD. Many more empirical studies are needed to unravel specific pathways and mechanisms that seem to link melanization with ARMD.
The retinal pigment epithilial (RPE) cells are responsible for the internalization and subsequent degradation of rod outer segments (ROS), which are shed daily from the distal ends of photoreceptors. The process of phagocytosis is complex and involves multiple steps involving recognition and attachment with various surface receptors [1-4], receptor-ligand interactions, and cytoskeletal rearrangement  with associated signaling and gene transduction mechanisms . The process of degradation of internalized ROS is equally complex, involving lysosome-phagosome fusion , breakdown, or recycling of the fatty acids of the ROS by lysosomal hydrolases and the generation of free radicals and superoxides.
Circumstantial evidence indicates that perturbations in either the rate of phagocytosis [8,9] and/or the rate of internalized ROS degradation in the RPE [10,11] ultimately lead to metabolic impairment of the cell and to severe consequences for the photoreceptors whose survival depends on a healthy RPE. For example, a decrease in the rate of phagocytosis may cause oxidation of rod outer segment lipid constituents before RPE binding and/or internalization occurs. The RPE lysosomal system may be incapable of efficiently degrading such oxidized lipid constituents [12,13] in part because they may perturb the fusion of lysosomes with phagosomes  thereby causing a decrease in the rate of ROS degradation. The mechanisms underlying vision loss in AMD are multifactorial, complex, and incompletely understood [15,16]. The early nonexudative form of the disease shows a predilection for parafoveal loss of rods over cones [17,18]. The spatial distribution of lipofuscin generally matches the parafoveal loss of rods in early AMD . Table 1 shows the possible permutations in the rate of phagocytosis (PR) or the rate of ROS degradation (RRD) along with the possible intracellular accumulation of lipofuscin. These permutations (in PR and RRD) are assumed to occur independently of each other, however, such may seldom be the case in vivo. An increase in the PR or/and a decrease in the RRD are factors that are most likely to cause an age related intracellular accumulation of lipofuscin .
Delayed or slower processing of internalized ROS has been associated in part with age related inactivation of lysosomal proteases [21-23]. Increases in intraphagosomal pH [24-26], lipofuscin accumulation , blocking phosphatidylinositol 3-kinase recruitment to the phagosomal membrane , increased susceptibility to oxidative processes , and decreases in antioxidant concentration have been proposed as some causative factors. Interestingly, vacuolar type H+ ATPase inhibitors that can act nonspecifically to increase the pH of intracellular organelles like phagosomes and melanosomes can cause a slower processing of ROS with a simultaneous increase in melanization [28-30], respectively.
Oxidative damage has been implicated in the etiology of age related macular degeneration [31-34]. Melanin may exert multiple effects against oxidative damage to RPE cells. It can scavenge free radicals [35-41]. The activities of lysosomal hydrolases are elevated in melanocytes engaged in melanin synthesis . It can prevent inactivation of lysosomal proteases in part by neutralizing 4-hydroxy-2-nonenal (HNE) that is generated by oxidation of low density lipoprotein [43,44]. It prevents lipid peroxidation [45,46] and hence may prevent oxidized lipoprotein (oxLDL) mediated inhibition of lysosomal fusion with phagosomes. Levels of A2E oxiranes and probably A2E were found to be substantially lower in pigmented abcr-/- mice when compared to albino abcr-/- mice due to attenuation of retinal illuminance by melanin . Lower levels of A2E may also prevent elevation of intraphagosomal pH [48,49] and the associated inactivation of lysosomal enzymes. By virtue of its metal chelating properties, it may prevent oxidative damage to the membranes of phagosomes and lysosomes and associated damage to the cytoskeleton myosin and actin fibers [50,51]. Melanin greatly reduces oxygen driven lipofuscin formation . Transgenic albino mice containing three point mutations in the opsin gene were observed to undergo a greater extent of photoreceptor degeneration than their age matched counterparts even when reared in darkness after birth . It therefore seems reasonable to assume that an increase in melanogenesis may simultaneously contribute to a decrease in PR and an increase in RRD, thereby reducing the rate of lipofuscin formation. For instance, although increased lipofuscin was found to correlate with photoreceptor loss, the accumulation of lipofuscin was not as strong a determinant of photoreceptor loss in blacks as it was in whites . Because the melanization of the RPE cell confers it such a broad range of protection against oxidative damage and also decreases the rate of rod outer segment photo-oxidation, the melanized RPE cell may be able to decrease its rate of phagocytosis of rod photoreceptor outer segments (ROS) without significant undesirable consequences. This decrease in ROS phagocytosis may serve to maintain a balance between ingestion and degradation/recycling thereby avoiding an increase to its already substantial metabolic load.
This review attempts to identify the signaling pathways that may link the upregulation of melanization to the downregulation of ROS phagocytosis. Mechanisms by which melanization, by itself, may contribute to a decrease in phagocytosis are identified. In the process, evidence is sought for the proposition that a decrease in ROS phagocytosis coupled with an increase in RPE melanization may have amiliorative effects in the onset and progression of age related macular degeneration.
Pathways and stimuli that exert opposite effects on melanization and phagocytosis
cAMP, PKC, and A2 adenosine receptors
Upregulation of cAMP, PKC, and A2 adenosine receptors has been shown to both increase melanization and decrease rod outer segment ingestion [55-59]. The adenylyl cyclase activator, forskolin, has been shown to inhibit tyrosine phosphorylation of a about 280 KDa protein that is essential for melatonin mediated melanosome aggregation .
Rats fed an α-Linolenic acid restricted diet showed a decrease in retinal lysosomal enzyme activity and a lower rod outer segment turnover rate , probably as a response to conserve the store of the important retinal constituent, docosahexaenoic acid (DHA) [62,63]. Restricted intake of (n-3) fatty acids has also been reported to decrease the adenosine dependent melatonin release in cultured rat pineal gland  and the rate of rhodopsin regeneration after bleaching , suggesting that the decrease in phagocytosis and the slowing of the visual cycle could be attributed at least in part to increased melanosome dispersion toward the apical microvilli processes of the RPE. Melanin dispersion toward the apical microvilli of the RPE correlates positively with the intracellular level of cAMP .
cAMP mediated increase in melanization may also be responsible for a decrease in ROS uptake in RPE cells on corneal endothelial extracellular cell matrices . Elevation of cAMP in macrophages has been shown to inhibit phagocytosis of apoptotic cells . Light has been shown to suppress cAMP synthesis in retinas of wild type mice . Forskolin, an adenylate cyclase (cAMP) stimulator, and theophylline, a phosphodiesterase inhibitor, both increase melanization of RPE and decrease ROS uptake .
ROS uptake of RPE cells grown on bovine corneal endothelial cell matrix (BCEM) and on tissue culture plastic with 44 mM NaHCO3 (an adenylate cyclase stimulator) was significantly less than ROS uptake of RPE cells grown on tissue culture plastic alone. Reduced ROS uptake in the earlier two cases was accompanied by increased melanization.
The phagocytosis of fibronectin coated beads was increased by PKC inhibitors . PKC inhibitors decrease melanization.
Phosphatidyl inositol-3 kinase pathway
Bovine ROS contain PI-3 kinase activity that is upregulated in light adapted retinas . This suggests that a partial abrogation of photon counts reaching the distal ends of photoreceptors may serve to downregulate PI-3 kinase activity and consequently phagocytosis. An increased melanin concentration in the apical microvilli of the RPE may decrease the photointensity reaching the distal ends of the photoreceptor outer rod segments [72-74]. Inhibitors of PI-3 kinase cause a decrease in phagocytosis , thereby implicating this enzyme, at least in part, in the modulation of phagocytosis through the activation of its downstream target, myosin X . Forskolin, a cAMP elevator, has been shown to exert its melanogenic activity at least in part through a downregulation of PI-3 kinase activity [77,78].
Nitric oxide pathway
Nitric oxide donors have been shown to induce melanogenesis in normal human epidermal keratinocytes . Nitric oxide also has been shown to decrease phagocytosis of bovine outer segments by RPE cells in vitro consistent with its role in inhibiting actin polymerization and causing melanophore aggregation .
Actin stress fiber formation has been shown to be controlled by the small GTP binding protein Rho . Rho inactivation has been shown to enhance the cAMP stimulation of tyrosinase gene expression and melanogenesis, while its constitutive activation impaired these cAMP induced effects in B16 melanoma cells . Rho has also been proposed to be an upstream regulator of both stress fiber formation and tyrosine phosphorylation of Focal Adhesion Kinase p125FAK. FAK expression has been shown to promote phagocytosis of integrin (α-v-β-5) bound photoreceptors . The inhibition of Rho can also be induced by α-MSH, which acts on the cAMP pathway. The parallel inhibition of FAK and the suppression of integrin expression leads to a decrease in phagocytosis with a simultaneous increase in pigmentation .
Persons carrying an apo-E4 allele show a decreased risk for AMD when compared with people homozygous for apo-E3 [85,86] and an increased risk for Alzheimer's disease . Apo-E- mice exhibit accumulation of electron lucent particles in Bruch's membrane at an earlier age and have more membrane bound material than controls [88,89]. The presence of apo-E in drusen and in basal laminar deposits has been demonstrated.
Although a direct effect of apo-E on pigmentation has not been reported, apo-E4 but not apo-E3, has been shown to activate an extracellular receptor kinase (ERK) cascade that results in activation of the cAMP responsive element binding protein (CREB) and an increase in the expression of downstream genes c-fos and Bcl-2 . Upregulation of cAMP, c-fos, and ERK pathways is known to increase melanization and decrease ROS phagocytosis.
Mechanisms by which melanization may decrease the rate of phagocytosis
Alteration of zeta potential
Melanization in fungi is associated with an increased negative surface charge per cell  that in turn is responsible in part for protection against phagocytic attack by host macrophages [92,93]. ROS phagocytosis has been shown to be mediated by the interaction of the scavenger receptor CD36 on the RPE with anionic phospholipids present on the surface of ROS membranes . Melanization of the RPE may decrease phagocytosis of rod outer segments due to increased electrostatic repulsion between these anionic lipids on the ROS membranes and the carboxy indole moieties, hydroquinone, or semiquinone sites on the melanin. Such a reduced rate of phagocytosis may enable the RPE cell to maintain the balance between ingestion and degradation/recycling so as to retard the formation of lipofuscin/drusen.
Reduction of photoisomerization events
The number of melanosomes in the apical processes surrounding adjacent photoreceptors of the mammalian RPE show a significant increase after light onset . An increase in melanization in the apical region may reduce the number of photons incident on the rod outer segments, thereby reducing the number of phototransduction or photoisomerization events.
A reduction of the light intensity reaching the photoreceptor outer rod segments may also decrease the rate of phototransduction events. This is analogous to the slowing of rhodopsin regeneration by isotretinoin that has been shown to protect photoreceptors from light damage and bleaching possibly by competing with RPE65 binding [96,97]. Reducing the number of photoisomerization events may also be beneficial in some genetic retinal diseases including Stargardt macular degeneration . Indeed, it has been shown that dark rearing of Abcr-/- mice prolongs rod cell survival by decreasing the retinoid turnover. A decrease of phototransduction events has also been shown to be beneficial in slowing down the visual cycle and preventing the formation of the major fluorophore of lipofuscin, A2E [97,99-101].
It is also reasonable to assume that the rate of phagocytosis may be controlled by phototransduction or photoisomerization events. Such a signaling mechanism may involve the cyclic nucleotide gated ion channels (CNG) on photoreceptor membranes that are modulated by cGMP. A phototransduction event leads to an activation cascade comprising rhodopsin, transducin, and cGMP-PDE. This phosphodiesterase breaks down cGMP, which causes the CNG channels to close and the photoreceptor cell to hyperpolarize, sending an electrical signal to the brain. Phosphodiesterase inhibitors such as theophylline, papaverine, and isobutylmethylxanthine have been shown to reduce ROS uptake and also simultaneously increase melanization, consistent with this hypothesis [69,102].
Decreasing subretinal Ca+2 concentration
Growth arrest specific (Gas6) protein is the ligand for the receptor protein tyrosine kinase, Mer . Gas6 can specifically and selectively stimulate the phagocytosis of photoreceptor outer segments by normal cultured rat RPE cells . Gas6 must bind to OS before the stimulation of OS ingestion can occur and this binding requires the presence of Ca+2 ions . The level of subretinal Ca+2 concentration has been shown to be negatively correlated with the level of RPE pigmentation because RPE melanin has been shown to bind calcium in direct proportion to the level of hypopigmentation of individual mouse strains [106,107]. It may be that melanization reduces Gas6 mediated phagocytosis by modulating calcium ion concentration in the subretinal space.
Reduction of metabolic burden mechanisms by which a decrease in the rate of photoreceptor phagocytosis may ameliorate the progression of AMD
Spatial topography, age relationship, and racial distributions of lipofuscin exhibit remarkably similarity to patterns seen in AMD . A positive correlation between the number of photoreceptors per RPE cell and elevated levels of lipofuscin has been observed . Lipofuscin is lower at the fovea than in the nasal or temporal macula [109,110]. Accumulation of choroidal lipids with age appears to be greater in the central than in the peripheral region of the fundus . Melanin is greatest at the fovea and decreases substantially from the fovea to about 5° eccentricity, exhibits a broad minimum between 5° and 20° and then increases slowly toward the equator [109,110]. The macular pigments lutein and zeaxanthein exhibit similar topographical concentrations, being highest at the center of the fovea and then diminishing with increasing eccentricity [112,113]. In addition to the beneficial antioxidant and free radical scavenging effects of these molecules at the fovea that may be partially responsible for its sparing in AMD, it has also been observed that the ratio of photoreceptors (rods and cones) to RPE cells was the lowest in the fovea and increased rapidly in the parafovea of the rhesus retina . It has been suggested that this significantly smaller photoreceptor to RPE cell ratio in the fovea places less metabolic demand on the RPE cells at this location [114,115]. The fewer foveal (cone derived) phagosomes as compared to extrafoveal (rod derived) phagosomes in the RPE of Rhesus monkeys may be a manifestation of this reduced metabolic demand in the fovea . This advantage may also contribute in part to the relative sparing of the foveal photoreceptors in aging and in some diseases of the retina [117-119]. As elucidated here, melanization appears to be negatively correlated with phagocytosis so that the increased melanization in the fovea may in part also contribute to lesser phagocytic burden on the RPE cells in this area. Figure 1 is a schematic depicting the concentration of melanin and lipofuscin and the ratio of number of photoreceptors per RPE cell plotted as a function of eccentricity.
Reduction of oxygen consumption
Photoreceptor cell phagocytosis by the RPE consumes oxygen . It has been proposed that the high oxygen consumption of dark adapted rod cells is the driving force of inner retinal hypoxia [121,122]. Oxygen tensions in the dark adapted rod cells have been found to be around 25 mmHg lower than those of light adapted ones at a distance of 100 μm from the choroid [123,124]. Hypoxia has been shown to upregulate vascular epidermal growth factor [125,126], which in turn has been implicated in choroidal neovascularization .
It has also been observed that diabetic retinopathy induced retinal neovascularization rarely occurs in retinitis pigmentosa patients [121,128-130]. The clinical success of panretinal photocoagulation in inhibiting neovascularization may also be attributed to the destruction by this procedure of a large number of photoreceptor cells and the reduction of intraocular VEGF levels . Ischemia induced neovascularization of the retina is abolished in a mouse strain with inherited photoreceptor cell degeneration . Lipofuscin deposition was found to decrease significantly in retinal degenerate rats only after photoreceptors were lost .
Taken together, these observations support the hypothesis that oxygen consumption associated with rod cell metabolism or the rate of rod outer segment phagocytosis  by the RPE may represent a major driving force in ischemic retinal neovascularization. This proposition suggests that reducing the rate of ROS phagocytosis may play a role in decreasing choroidal neovascularization.
Drugs modulating melanization and phagocytosis
cAMP elevating agents [135,136], phosphodiesterase inhibitors, visual cycle slowing agents, cytoskeleton disruptors, lysomotropic agents , agents that affect cellular charge, certain prostaglandins may be reasonably expected to decrease the rate of ROS phagocytosis and increase melanization of RPE.
Although most approved or experimental drugs for ARMD target the vascular endothelial growth factor or are anti-angiogenic agents, there are several investigational drugs in preclinical or clinical trials that are capable of decreasing the rate of ROS phagocytosis by the RPE. Some examples are: (1) an α-5-β-1 integrin antibody fragment (Protein Design Labs, Fremont, CA), (2) integrin antagonists (Jerini, Berlin, Germany), (3) bFGF-2 vaccine (Entremed, Rockville, MD), isotretinoin (UCLA, Los Angeles, CA) and (4) a phosphodiesterase-5 inhibitor (Pfizer, Groton, CT).
Several important questions need to be addressed to better understand the role of the rate of ROS phagocytosis on the onset and progression of AMD. The role that pigmentation plays in modulating the rate of ROS phagocytosis and therefore subsequent ROS degradation also needs further empirical analysis. In general the following may be worthy of further exploration:
1. Does increased melanogenesis decrease phagocytosis of rod outer segments?
2. Does increased melanization decrease the rate of intracellular degradation of rod outer segments?
3. Are RPE melanin levels elevated in macular degeneration relative to age matched controls?
4. Does increased melanin dispersion within the melanosome (i.e., more melanin present in the microvilli) decrease the rate of rod outer segment photo-oxidation and/or the rate of photoisomerization events?
5. Does decreasing the rate of ROS phagocytosis reduce lipofuscin formation and Drusen formation?
Several lines of evidence suggest that the pathways by which melanization and phagocytosis are activated are inextricably linked such that the overall effect seems to be that a downregulation of one causes an upregulation of the other. Such an effect may be reasonably anticipated since an increase in melanization in the apical RPE region contributes to an effective blocking and absorption of light reaching the rod outer segments (ROS). A reduction in light intensity is expected to decrease the photo-oxidation of the long chain fatty acids comprising the photoreceptor outer segment that may decrease the rate of phagocytosis.
Mammalian melanogenesis is regulated directly or indirectly by more than 95 distinct loci [138,139]. The melanization inducing gene Mitf also modulates expression levels of growth factors and intracellular proteins that cause a decrease in phagocytosis. In addition, cellular signals that modulate melanogenesis, phagocytosis and immune response share common receptors, genes or their transcription factors such as cfos, PI-3 kinase, MAP-K, cAMP, FAK, α-MSH, PKC, Punch, Pale, PPAR, CD36, Rho, and NF-kB. What factors could be responsible for packaging these different evolutionary traits (increased melanogenesis and decreased phagocytosis, for example) on the same genome? One possible explanation is that such packaging of dissimilar traits represents an evolutionary response to preventing increases in the already substantial ingestion rates of ROS by the RPE  in tropical regions or high photo-intense areas of the planet. Increased melanization may have constituted part of the response.
The above may also explain why these different genetic traits have partially overlapping signaling pathways so that activation of one gene results in the fortuitous modulation of the others. In this context, it is reasonably apparent that a decrease of photoreceptor phagocytosis by the RPE may be sustainable only when it is accompanied by a comparable decrease in photoreceptor photo-oxidation. Such a decrease in outer segment photo-oxidation can be attributed to increased melanization.
Rather than relegating melanization simply as a "marker" for a variety of pathophysiological disorders, its modulation by pharmacological agents can be used to constructively disrupt correlated phagocytic, angiogenic, and immune response signaling mechanisms as elucidated in this manuscript. In summary, the proposition that the onset and/or progression of AMD may be delayed by decreasing the rate of ROS phagocytosis may be worthy of further research. Many more empirical studies are needed to unravel specific pathways and mechanisms that seem to link pigmentation with other important ocular anabolic and metabolic processes.
1. Boyle D, Tien LF, Cooper NG, Shepherd V, McLaughlin BJ. A mannose receptor is involved in retinal phagocytosis. Invest Ophthalmol Vis Sci 1991; 32:1464-70.
2. Ryeom SW, Sparrow JR, Silverstein RL. CD36 participates in the phagocytosis of rod outer segments by retinal pigment epithelium. J Cell Sci 1996; 109:387-95.
3. Nguyen-Legros J, Hicks D. Renewal of photoreceptor outer segments and their phagocytosis by the retinal pigment epithelium. Int Rev Cytol 2000; 196:245-313.
4. D'Cruz PM, Yasumura D, Weir J, Matthes MT, Abderrahim H, LaVail MM, Vollrath D. Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Hum Mol Genet 2000; 9:645-51.
5. Chaitin MH, Hall MO. The distribution of actin in cultured normal and dystrophic rat pigment epithelial cells during the phagocytosis of rod outer segments. Invest Ophthalmol Vis Sci 1983; 24:821-31.
6. Chowers I, Kim Y, Farkas RH, Gunatilaka TL, Hackam AS, Campochiaro PA, Finnemann SC, Zack DJ. Changes in retinal pigment epithelial gene expression induced by rod outer segment uptake. Invest Ophthalmol Vis Sci 2004; 45:2098-106.
7. Bosch E, Horwitz J, Bok D. Phagocytosis of outer segments by retinal pigment epithelium: phagosome-lysosome interaction. J Histochem Cytochem 1993; 41:253-63.
8. Gal A, Li Y, Thompson DA, Weir J, Orth U, Jacobson SG, Apfelstedt-Sylla E, Vollrath D. Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat Genet 2000; 26:270-1.
9. Vollrath D, Feng W, Duncan JL, Yasumura D, D'Cruz PM, Chappelow A, Matthes MT, Kay MA, LaVail MM. Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk. Proc Natl Acad Sci U S A 2001; 98:12584-9.
10. Sun H, Nathans J. The challenge of macular degeneration. Sci Am 2001; 285:68-75.
11. Finnemann SC, Leung LW, Rodriguez-Boulan E. The lipofuscin component A2E selectively inhibits phagolysosomal degradation of photoreceptor phospholipid by the retinal pigment epithelium. Proc Natl Acad Sci U S A 2002; 99:3842-7.
12. Becquet F, Goureau O, Soubrane G, Coscas G, Courtois Y, Hicks D. Superoxide inhibits proliferation and phagocytic internalization of photoreceptor outer segments by bovine retinal pigment epithelium in vitro. Exp Cell Res 1994; 212:374-82.
13. Wihlmark U, Wrigstad A, Roberg K, Brunk UT, Nilsson SE. Formation of lipofuscin in cultured retinal pigment epithelial cells exposed to pre-oxidized photoreceptor outer segments. APMIS 1996; 104:272-9.
14. Hoppe G, Marmorstein AD, Pennock EA, Hoff HF. Oxidized low density lipoprotein-induced inhibition of processing of photoreceptor outer segments by RPE. Invest Ophthalmol Vis Sci 2001; 42:2714-20.
15. Zarbin MA. Age-related macular degeneration: review of pathogenesis. Eur J Ophthalmol 1998; 8:199-206.
16. Bird A. Age-related macular disease. Br J Ophthalmol 1996; 80:2-3.
17. Curcio CA, Owsley C, Jackson GR. Spare the rods, save the cones in aging and age-related maculopathy. Invest Ophthalmol Vis Sci 2000; 41:2015-8.
18. Curcio CA, Millican CL, Allen KA, Kalina RE. Aging of the human photoreceptor mosaic: evidence for selective vulnerability of rods in central retina. Invest Ophthalmol Vis Sci 1993; 34:3278-96.
19. Wing GL, Blanchard GC, Weiter JJ. The topography and age relationship of lipofuscin concentration in the retinal pigment epithelium. Invest Ophthalmol Vis Sci 1978; 17:601-7.
20. Bird AC. What is the future of research in age-related macular disease? Arch Ophthalmol 1997; 115:1311-3.
21. Kennedy CJ, Rakoczy PE, Robertson TA, Papadimitriou JM, Constable IJ. Kinetic studies on phagocytosis and lysosomal digestion of rod outer segments by human retinal pigment epithelial cells in vitro. Exp Cell Res 1994; 210:209-14.
22. Rakoczy P, Constable IJ. Pathogenesis of macular degeneration: is there any progress? Aust N Z J Ophthalmol 1998; 26:67-70.
23. Rakoczy PE, Lai CM, Baines M, Di Grandi S, Fitton JH, Constable IJ. Modulation of cathepsin D activity in retinal pigment epithelial cells. Biochem J 1997; 324:935-40.
24. Deguchi J, Yamamoto A, Yoshimori T, Sugasawa K, Moriyama Y, Futai M, Suzuki T, Kato K, Uyama M, Tashiro Y. Acidification of phagosomes and degradation of rod outer segments in rat retinal pigment epithelium. Invest Ophthalmol Vis Sci 1994; 35:568-79.
25. Mousavi SA, Kjeken R, Berg TO, Seglen PO, Berg T, Brech A. Effects of inhibitors of the vacuolar proton pump on hepatic heterophagy and autophagy. Biochim Biophys Acta 2001; 1510:243-57.
26. Schutt F, Davies S, Kopitz J, Holz FG, Boulton ME. Photodamage to human RPE cells by A2-E, a retinoid component of lipofuscin. Invest Ophthalmol Vis Sci 2000; 41:2303-8.
27. Sundelin S, Wihlmark U, Nilsson SE, Brunk UT. Lipofuscin accumulation in cultured retinal pigment epithelial cells reduces their phagocytic capacity. Curr Eye Res 1998; 17:851-7.
28. Manga P, Orlow SJ. Inverse correlation between pink-eyed dilution protein expression and induction of melanogenesis by bafilomycin A1. Pigment Cell Res 2001; 14:362-7.
29. Ancans J, Tobin DJ, Hoogduijn MJ, Smit NP, Wakamatsu K, Thody AJ. Melanosomal pH controls rate of melanogenesis, eumelanin/phaeomelanin ratio and melanosome maturation in melanocytes and melanoma cells. Exp Cell Res 2001; 268:26-35.
30. Fuller BB, Spaulding DT, Smith DR. Regulation of the catalytic activity of preexisting tyrosinase in black and Caucasian human melanocyte cell cultures. Exp Cell Res 2001; 262:197-208.
31. Crabb JW, Miyagi M, Gu X, Shadrach K, West KA, Sakaguchi H, Kamei M, Hasan A, Yan L, Rayborn ME, Salomon RG, Hollyfield JG. Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci U S A 2002; 99:14682-7.
32. Winkler BS, Boulton ME, Gottsch JD, Sternberg P. Oxidative damage and age-related macular degeneration. Mol Vis 1999; 5:32 <http://www.molvis.org/molvis/v5/a32/>.
33. Cai J, Nelson KC, Wu M, Sternberg P Jr, Jones DP. Oxidative damage and protection of the RPE. Prog Retin Eye Res 2000; 19:205-21.
34. Liang FQ, Godley BF. Oxidative stress-induced mitochondrial DNA damage in human retinal pigment epithelial cells: a possible mechanism for RPE aging and age-related macular degeneration. Exp Eye Res 2003; 76:397-403.
35. Korytowski W, Sarna T, Zar ba M. Antioxidant action of neuromelanin: the mechanism of inhibitory effect on lipid peroxidation. Arch Biochem Biophys 1995; 319:142-8.
36. Zareba M, Bober A, Korytowski W, Zecca L, Sarna T. The effect of a synthetic neuromelanin on yield of free hydroxyl radicals generated in model systems. Biochim Biophys Acta 1995; 1271:343-8.
37. Sealy RC, Sarna T, Wanner EJ, Reszka K. Photosensitization of melanin: an electron spin resonance study of sensitized radical production and oxygen consumption. Photochem Photobiol 1984; 40:453-9.
38. Sarna T, Menon IA, Sealy RC. Photosensitization of melanins: a comparative study. Photochem Photobiol 1985; 42:529-32.
39. Sarna T, Pilas B, Land EJ, Truscott TG. Interaction of radicals from water radiolysis with melanin. Biochim Biophys Acta 1986; 883:162-7.
40. Geremia E, Corsaro C, Bonomo R, Giardinelli R, Pappalardo P, Vanella A, Sichel G. Eumelanins as free radical trap and superoxide dismutase activity in Amphibia. Comp Biochem Physiol B 1984; 79:67-9.
41. Korytowski W, Kalyanaraman B, Menon IA, Sarna T, Sealy RC. Reaction of superoxide anions with melanins: electron spin resonance and spin trapping studies. Biochim Biophys Acta 1986; 882:145-53.
42. Diment S, Eidelman M, Rodriguez GM, Orlow SJ. Lysosomal hydrolases are present in melanosomes and are elevated in melanizing cells. J Biol Chem 1995; 270:4213-5.
43. Stepien K, Wilczok A, Zajdel A, Dzierzega-Lecznar A, Wilczok T. Peroxynitrite mediated linoleic acid oxidation and tyrosine nitration in the presence of synthetic neuromelanins. Acta Biochim Pol 2000; 47:931-40.
44. Crabb JW, O'Neil J, Miyagi M, West K, Hoff HF. Hydroxynonenal inactivates cathepsin B by forming Michael adducts with active site residues. Protein Sci 2002; 11:831-40.
45. Sarna T, Rozanowska M, Zareba M, Wielgus A. Mechanisms of melanin photoprotection: inhibition of lipid peroxidation by ocular melanin. 9th Congress of the European Society for Photobiology; 2001 Sep 3-8; Lillehammer, Norway.
46. Kayatz P, Esser P, Peters S, Schraermeyer U. Ultrastructural localization of lipid peroxides in the choroid of the albino mouse. 96th Deutsche Ophthalmologische Gesellschaft Annual Meeting; 1998 Sep 19-22; Berlin, Germany.
47. Radu RA, Mata NL, Bagla A, Travis GH. Light exposure stimulates formation of A2E oxiranes in a mouse model of Stargardt's macular degeneration. Proc Natl Acad Sci U S A 2004; 101:5928-33.
48. Schutt F, Bergmann M, Kopitz J, Holz FG. [Mechanism of the inhibition of lysosomal functions in the retinal pigment epithelium by lipofuscin retinoid component A2-E]. Ophthalmologe 2001; 98:721-4.
49. Bergmann M, Schutt F, Holz FG, Kopitz J. Inhibition of the ATP-driven proton pump in RPE lysosomes by the major lipofuscin fluorophore A2-E may contribute to the pathogenesis of age-related macular degeneration. FASEB J 2004; 18:562-4.
50. Akeo K, Hiramitsu T, Yorifuji H, Okisaka S. Membranes of retinal pigment epithelial cells in vitro are damaged in the phagocytotic process of the photoreceptor outer segment discs peroxidized by ferrous ions. Pigment Cell Res 2002; 15:341-7.
51. Hahn P, Milam AH, Dunaief JL. Maculas affected by age-related macular degeneration contain increased chelatable iron in the retinal pigment epithelium and Bruch's membrane. Arch Ophthalmol 2003; 121:1099-105.
52. Sundelin SP, Nilsson SE, Brunk UT. Lipofuscin-formation in cultured retinal pigment epithelial cells is related to their melanin content. Free Radic Biol Med 2001; 30:74-81.
53. Naash MI, Ripps H, Li S, Goto Y, Peachey NS. Polygenic disease and retinitis pigmentosa: albinism exacerbates photoreceptor degeneration induced by the expression of a mutant opsin in transgenic mice. J Neurosci 1996; 16:7853-8.
54. Dorey CK, Wu G, Ebenstein D, Garsd A, Weiter JJ. Cell loss in the aging retina. Relationship to lipofuscin accumulation and macular degeneration. Invest Ophthalmol Vis Sci 1989; 30:1691-9.
55. Rossi AG, McCutcheon JC, Roy N, Chilvers ER, Haslett C, Dransfield I. Regulation of macrophage phagocytosis of apoptotic cells by cAMP. J Immunol 1998; 160:3562-8.
56. Eckmiller MS, Burnside B. Light-induced photoreceptor shedding in teleost retina blocked by dibutyryl cyclic AMP. Invest Ophthalmol Vis Sci 1983; 24:1328-32.
57. Gregory CY, Abrams TA, Hall MO. Stimulation of A2 adenosine receptors inhibits the ingestion of photoreceptor outer segments by retinal pigment epithelium. Invest Ophthalmol Vis Sci 1994; 35:819-25.
58. Hall MO, Abrams TA, Mittag TW. ROS ingestion by RPE cells is turned off by increased protein kinase C activity and by increased calcium. Exp Eye Res 1991; 52:591-8.
59. Hu DN, McCormick SA, Orlow SJ, Rosemblat S, Lin AY. Regulation of melanogenesis by human uveal melanocytes in vitro. Exp Eye Res 1997; 64:397-404.
60. Karlsson AM, Lerner MR, Unett D, Lundstrom I, Svensson SP. Melatonin-induced organelle movement in melanophores is coupled to tyrosine phosphorylation of a high molecular weight protein. Cell Signal 2000; 12:469-74.
61. Ikemoto A, Fukuma A, Fujii Y, Okuyama H. Lysosomal enzyme activities are decreased in the retina and their circadian rhythms are different from those in the pineal gland of rats fed an alpha-linolenic acid-restricted diet. J Nutr 2000; 130:3059-62.
62. Fliesler SJ, Anderson RE. Chemistry and metabolism of lipids in the vertebrate retina. Prog Lipid Res 1983; 22:79-131.
63. Baker BN, Moriya M, Maude MB, Anderson RE, Williams TP. Oil droplets of the retinal epithelium of the rat. Exp Eye Res 1986; 42:547-57.
64. Gazzah N, Gharib A, Delton I, Moliere P, Durand G, Christon R, Lagarde M, Sarda N. Effect of an n-3 fatty acid-deficient diet on the adenosine-dependent melatonin release in cultured rat pineal. J Neurochem 1993; 61:1057-63.
65. Bush RA, Malnoe A, Reme CE, Williams TP. Dietary deficiency of N-3 fatty acids alters rhodopsin content and function in the rat retina. Invest Ophthalmol Vis Sci 1994; 35:91-100.
66. Reilein AR, Tint IS, Peunova NI, Enikolopov GN, Gelfand VI. Regulation of organelle movement in melanophores by protein kinase A (PKA), protein kinase C (PKC), and protein phosphatase 2A (PP2A). J Cell Biol 1998; 142:803-13.
67. Miceli MV, Newsome DA. Effects of extracellular matrix and Bruch's membrane on retinal outer segment phagocytosis by cultured human retinal pigment epithelium. Curr Eye Res 1996; 15:17-26. Erratum in: Curr Eye Res 1996; 15:804-5.
68. Nir I, Harrison JM, Haque R, Low MJ, Grandy DK, Rubinstein M, Iuvone PM. Dysfunctional light-evoked regulation of cAMP in photoreceptors and abnormal retinal adaptation in mice lacking dopamine D4 receptors. J Neurosci 2002; 22:2063-73.
69. Edwards RB, Bakshian S. Phagocytosis of outer segments by cultured rat pigment epithelium. Reduction by cyclic AMP and phosphodiesterase inhibitors. Invest Ophthalmol Vis Sci 1980; 19:1184-8.
70. Zhao MW, Jin ML, He S, Spee C, Ryan SJ, Hinton DR. A distinct integrin-mediated phagocytic pathway for extracellular matrix remodeling by RPE cells. Invest Ophthalmol Vis Sci 1999; 40:2713-23.
71. Guo X, Ghalayini AJ, Chen H, Anderson RE. Phosphatidylinositol 3-kinase in bovine photoreceptor rod outer segments. Invest Ophthalmol Vis Sci 1997; 38:1873-82.
72. King-Smith C, Chen P, Garcia D, Rey H, Burnside B. Calcium-independent regulation of pigment granule aggregation and dispersion in teleost retinal pigment epithelial cells. J Cell Sci 1996; 109:33-43.
73. Murray RL, Dubin MW. The occurrence of actinlike filaments in association with migrating pigment granules in frog retinal pigment epithelium. J Cell Biol 1975; 64:705-10.
74. Kim IT, Choi JB. Melanosomes of retinal pigment epithelium--distribution, shape, and acid phosphatase activity. Korean J Ophthalmol 1998; 12:85-91.
75. Greenberg S, Chang P, Wang DC, Xavier R, Seed B. Clustered syk tyrosine kinase domains trigger phagocytosis. Proc Natl Acad Sci U S A 1996; 93:1103-7.
76. Cox D, Berg JS, Cammer M, Chinegwundoh JO, Dale BM, Cheney RE, Greenberg S. Myosin X is a downstream effector of PI(3)K during phagocytosis. Nat Cell Biol 2002; 4:469-77.
77. Busca R, Bertolotto C, Ortonne JP, Ballotti R. Inhibition of the phosphatidylinositol 3-kinase/p70(S6)-kinase pathway induces B16 melanoma cell differentiation. J Biol Chem 1996; 271:31824-30.
78. Tsatmali M, Ancans J, Thody AJ. Melanocyte function and its control by melanocortin peptides. J Histochem Cytochem 2002; 50:125-33.
79. Romero-Graillet C, Aberdam E, Biagoli N, Massabni W, Ortonne JP, Ballotti R. Ultraviolet B radiation acts through the nitric oxide and cGMP signal transduction pathway to stimulate melanogenesis in human melanocytes. J Biol Chem 1996; 271:28052-6.
80. Nilsson HM, Karlsson AM, Loitto VM, Svensson SP, Sundqvist T. Nitric oxide modulates intracellular translocation of pigment organelles in Xenopus laevis melanophores. Cell Motil Cytoskeleton 2000; 47:209-18.
81. Wang F, Nobes CD, Hall A, Spiegel S. Sphingosine 1-phosphate stimulates rho-mediated tyrosine phosphorylation of focal adhesion kinase and paxillin in Swiss 3T3 fibroblasts. Biochem J 1997; 324:481-8.
82. Busca R, Bertolotto C, Abbe P, Englaro W, Ishizaki T, Narumiya S, Boquet P, Ortonne JP, Ballotti R. Inhibition of Rho is required for cAMP-induced melanoma cell differentiation. Mol Biol Cell 1998; 9:1367-78.
83. Finnemann SC. Focal adhesion kinase signaling promotes phagocytosis of integrin-bound photoreceptors. EMBO J 2003; 22:4143-54.
84. Zhu N, Eves PC, Katerinaki E, Szabo M, Morandini R, Ghanem G, Lorigan P, MacNeil S, Haycock JW. Melanoma cell attachment, invasion, and integrin expression is upregulated by tumor necrosis factor alpha and suppressed by alpha melanocyte stimulating hormone. J Invest Dermatol 2002; 119:1165-71.
85. Klaver CC, Kliffen M, van Duijn CM, Hofman A, Cruts M, Grobbee DE, van Broeckhoven C, de Jong PT. Genetic association of apolipoprotein E with age-related macular degeneration. Am J Hum Genet 1998; 63:200-6. Erratum in: Am J Hum Genet 1998; 63:1252.
86. Simonelli F, Margaglione M, Testa F, Cappucci G, Manitto MP, Brancato R, Rinaldi E. Apolipoprotein E polymorphisms in age-related macular degeneration in an Italian population. Ophthalmic Res 2001; 33:325-8.
87. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993; 261:921-3.
88. Dithmar S, Curcio CA, Le NA, Brown S, Grossniklaus HE. Ultrastructural changes in Bruch's membrane of apolipoprotein E-deficient mice. Invest Ophthalmol Vis Sci 2000; 41:2035-42.
89. Ong JM, Zorapapel NC, Rich KA, Wagstaff RE, Lambert RW, Rosenberg SE, Moghaddas F, Pirouzmanesh A, Aoki AM, Kenney MC. Effects of cholesterol and apolipoprotein E on retinal abnormalities in ApoE-deficient mice. Invest Ophthalmol Vis Sci 2001; 42:1891-900.
90. Ohkubo N, Mitsuda N, Tamatani M, Yamaguchi A, Lee YD, Ogihara T, Vitek MP, Tohyama M. Apolipoprotein E4 stimulates cAMP response element-binding protein transcriptional activity through the extracellular signal-regulated kinase pathway. J Biol Chem 2001; 276:3046-53.
91. Nosanchuk JD, Casadevall A. Cellular charge of Cryptococcus neoformans: contributions from the capsular polysaccharide, melanin, and monoclonal antibody binding. Infect Immun 1997; 65:1836-41.
92. Casadevall A, Rosas AL, Nosanchuk JD. Melanin and virulence in Cryptococcus neoformans. Curr Opin Microbiol 2000; 3:354-8.
93. Nosanchuk JD, Cleare W, Franzot SP, Casadevall A. Amphotericin B and fluconazole affect cellular charge, macrophage phagocytosis, and cellular morphology of Cryptococcus neoformans at subinhibitory concentrations. Antimicrob Agents Chemother 1999; 43:233-9.
94. Ryeom SW, Silverstein RL, Scotto A, Sparrow JR. Binding of anionic phospholipids to retinal pigment epithelium may be mediated by the scavenger receptor CD36. J Biol Chem 1996; 271:20536-9.
95. Futter CE, Ramalho JS, Jaissle GB, Seeliger MW, Seabra MC. The role of Rab27a in the regulation of melanosome distribution within retinal pigment epithelial cells. Mol Biol Cell 2004; 15:2264-75.
96. Gollapalli DR, Rando RR. The specific binding of retinoic acid to RPE65 and approaches to the treatment of macular degeneration. Proc Natl Acad Sci U S A 2004; 101:10030-5.
97. Katz ML, Redmond TM. Effect of Rpe65 knockout on accumulation of lipofuscin fluorophores in the retinal pigment epithelium. Invest Ophthalmol Vis Sci 2001; 42:3023-30.
98. Sieving PA, Chaudhry P, Kondo M, Provenzano M, Wu D, Carlson TJ, Bush RA, Thompson DA. Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy. Proc Natl Acad Sci U S A 2001; 98:1835-40.
99. Radu RA, Mata NL, Nusinowitz S, Liu X, Sieving PA, Travis GH. Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration. Proc Natl Acad Sci U S A 2003; 100:4742-7.
100. Sparrow JR. Therapy for macular degeneration: insights from acne. Proc Natl Acad Sci U S A 2003; 100:4353-4.
101. Baehr W, Wu SM, Bird AC, Palczewski K. The retinoid cycle and retina disease. Vision Res 2003; 43:2957-8.
102. Imokawa G, Yada Y, Kimura M. Signalling mechanisms of endothelin-induced mitogenesis and melanogenesis in human melanocytes. Biochem J 1996; 314:305-12.
103. Manfioletti G, Brancolini C, Avanzi G, Schneider C. The protein encoded by a growth arrest-specific gene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade. Mol Cell Biol 1993; 13:4976-85.
104. Hall MO, Prieto AL, Obin MS, Abrams TA, Burgess BL, Heeb MJ, Agnew BJ. Outer segment phagocytosis by cultured retinal pigment epithelial cells requires Gas6. Exp Eye Res 2001; 73:509-20.
105. Hall MO, Obin MS, Prieto AL, Burgess BL, Abrams TA. Gas6 binding to photoreceptor outer segments requires gamma-carboxyglutamic acid (Gla) and Ca(2+) and is required for OS phagocytosis by RPE cells in vitro. Exp Eye Res 2002; 75:391-400.
106. Drager UC. Calcium binding in pigmented and albino eyes. Proc Natl Acad Sci U S A 1985; 82:6716-20.
107. Lavallee CR, Chalifoux JR, Moosally AJ, Balkema GW. Elevated free calcium levels in the subretinal space elevate the absolute dark-adapted threshold in hypopigmented mice. J Neurophysiol 2003; 90:3654-62.
108. Dorey CK, Staurenghi G, Delori FC. Lipofuscin in aged and AMD eyes. In: Hollyfield JG, Anderson RE, LaVail MM, editors. Retinal Degeneration: clinical and laboratory applications. New York: Plenum Press; 1993. pp. 3-14.
109. Weiter JJ, Delori FC, Wing GL, Fitch KA. Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes. Invest Ophthalmol Vis Sci 1986; 27:145-52.
110. Feeney-Burns L, Hilderbrand ES, Eldridge S. Aging human RPE: morphometric analysis of macular, equatorial, and peripheral cells. Invest Ophthalmol Vis Sci 1984; 25:195-200.
111. Holz FG, Sheraidah G, Pauleikhoff D, Bird AC. Analysis of lipid deposits extracted from human macular and peripheral Bruch's membrane. Arch Ophthalmol 1994; 112:402-6.
112. Beatty S, Boulton M, Henson D, Koh HH, Murray IJ. Macular pigment and age related macular degeneration. Br J Ophthalmol 1999; 83:867-77.
113. Snodderly DM, Auran JD, Delori FC. The macular pigment. II. Spatial distribution in primate retinas. Invest Ophthalmol Vis Sci 1984; 25:674-85.
114. Snodderly DM, Sandstrom MM, Leung IY, Zucker CL, Neuringer M. Retinal pigment epithelial cell distribution in central retina of rhesus monkeys. Invest Ophthalmol Vis Sci 2002; 43:2815-8.
115. Robinson SR, Hendrickson A. Shifting relationships between photoreceptors and pigment epithelial cells in monkey retina: implications for the development of retinal topography. Vis Neurosci 1995; 12:767-78.
116. Anderson DH, Fisher SK, Erickson PA, Tabor GA. Rod and cone disc shedding in the rhesus monkey retina: a quantitative study. Exp Eye Res 1980; 30:559-74.
117. Curcio CA. Photoreceptor topography in ageing and age-related maculopathy. Eye 2001; 15:376-83.
118. Weiter JJ, Delori F, Dorey CK. Central sparing in annular macular degeneration. Am J Ophthalmol 1988; 106:286-92.
119. Berson EL. Retinitis pigmentosa. The Friedenwald Lecture. Invest Ophthalmol Vis Sci 1993; 34:1659-76.
120. Miceli MV, Liles MR, Newsome DA. Evaluation of oxidative processes in human pigment epithelial cells associated with retinal outer segment phagocytosis. Exp Cell Res 1994; 214:242-9.
121. Arden GB. The absence of diabetic retinopathy in patients with retinitis pigmentosa: implications for pathophysiology and possible treatment. Br J Ophthalmol 2001; 85:366-70.
122. Linsenmeier RA. Effects of light and darkness on oxygen distribution and consumption in the cat retina. J Gen Physiol 1986; 88:521-42.
123. Linsenmeier RA, Braun RD. Oxygen distribution and consumption in the cat retina during normoxia and hypoxemia. J Gen Physiol 1992; 99:177-97.
124. Braun RD, Linsenmeier RA, Goldstick TK. Oxygen consumption in the inner and outer retina of the cat. Invest Ophthalmol Vis Sci 1995; 36:542-54.
125. Pierce EA, Avery RL, Foley ED, Aiello LP, Smith LE. Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc Natl Acad Sci U S A 1995; 92:905-9.
126. Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L, Ferrara N, King GL, Smith LE. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci U S A 1995; 92:10457-61.
127. Duh E, Aiello LP. Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox. Diabetes 1999; 48:1899-906.
128. Pruett RC. Retinitis pigmentosa: clinical observations and correlations. Trans Am Ophthalmol Soc 1983; 81:693-735.
129. Uliss AE, Gregor ZJ, Bird AC. Retinitis pigmentosa and retinal neovascularization. Ophthalmology 1986; 93:1599-603.
130. Hayakawa M, Hotta Y, Imai Y, Fujiki K, Nakamura A, Yanashima K, Kanai A. Clinical features of autosomal dominant retinitis pigmentosa with rhodopsin gene codon 17 mutation and retinal neovascularization in a Japanese patient. Am J Ophthalmol 1993; 115:168-73.
131. Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE, Nguyen HV, Aiello LM, Ferrara N, King GL. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994; 331:1480-7.
132. Lahdenranta J, Pasqualini R, Schlingemann RO, Hagedorn M, Stallcup WB, Bucana CD, Sidman RL, Arap W. An anti-angiogenic state in mice and humans with retinal photoreceptor cell degeneration. Proc Natl Acad Sci U S A 2001; 98:10368-73.
133. Katz ML, Drea CM, Eldred GE, Hess HH, Robison WG Jr. Influence of early photoreceptor degeneration on lipofuscin in the retinal pigment epithelium. Exp Eye Res 1986; 43:561-73.
134. Yu DY, Cringle SJ. Oxygen distribution and consumption within the retina in vascularised and avascular retinas and in animal models of retinal disease. Prog Retin Eye Res 2001; 20:175-208.
135. Hall MO, Abrams TA, Mittag TW. The phagocytosis of rod outer segments is inhibited by drugs linked to cyclic adenosine monophosphate production. Invest Ophthalmol Vis Sci 1993; 34:2392-401.
136. Kuriyama S, Hall MO, Abrams TA, Mittag TW. Isoproterenol inhibits rod outer segment phagocytosis by both cAMP-dependent and independent pathways. Invest Ophthalmol Vis Sci 1995; 36:730-6.
137. Mannerstrom M, Maenpaa H, Toimela T, Salminen L, Tahti H. The phagocytosis of rod outer segments is inhibited by selected drugs in retinal pigment epithelial cell cultures. Pharmacol Toxicol 2001; 88:27-33.
138. Doolittle DP, Davisson MT, Guidi JN, Green MC. Catalog of mutant genes and polymorphic loci. In: Lyon MF, Rastan S, Brown SDM, editors. Genetic variants and strains of the laboratory mouse. Oxford: Oxford University Press; 1996. pp. 17-854.
139. Jackson IJ. Homologous pigmentation mutations in human, mouse and other model organisms. Hum Mol Genet 1997; 6:1613-24.
140. Travis GH. Mechanisms of cell death in the inherited retinal degenerations. Am J Hum Genet 1998; 62:503-8.