The Placental Growth Factor Pathway and Its Potential Role in Macular Degenerative Disease

References

• Wong WL, Su X, Li X, Cheung CMG, Klein R, Cheng CY, Wong TY. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis. Lancet Glob Heal. 2014;2:e106–e116. doi:10.1016/S2214-109X(13)70145-1.
   PubMed Web of Science ®Google Scholar
• Sarks SH, Arnold JJ, Killingsworth MC, Sarks JP. Early drusen formation in the normal and aging eye and their relation to age related maculopathy: a clinicopathological study. Br J Ophthalmol. 1999;83:358–68. doi:10.1136/bjo.83.3.358.
   PubMed Web of Science ®Google Scholar
• Klein R, Klein BEK, Knudtson MD, Meuer SM, Swift M, Gangnon RE. Fifteen-year cumulative incidence of age-related macular degeneration. The beaver dam eye study. Ophthalmology. 2007;114(2):253–62. doi:10.1016/j.ophtha.2006.10.040.
   PubMed Web of Science ®Google Scholar
• Wang L, Clark ME, Crossman DK, Kojima K, Messinger JD, Mobley JA, Curcio CA. Abundant lipid and protein components of Drusen Koch K-W, editor. PLoS One. 2010;5(4):e10329. doi:10.1371/journal.pone.0010329.
   PubMed Web of Science ®Google Scholar
• Boyer NP, Tang PH, Higbee D, Ablonczy Z, Crouch RK, Koutalos Y. Lipofuscin and A2E accumulate with age in the retinal pigment epithelium of Nrl −/− Mice. Photochem Photobiol. 2012;88(6):1373–77. doi:10.1111/j.1751-1097.2012.01127.x.
   PubMed Web of Science ®Google Scholar
• Glenn JV, Mahaffy H, Wu K, Smith G, Nagai R, Simpson DAC, Boulton ME, Stitt AW. Advanced glycation end product (AGE) accumulation on Bruch’s membrane: links to age-related RPE dysfunction. Investig Ophthalmol Vis Sci. 2009;50(1):441–51. doi:10.1167/iovs.08-1724.
   PubMed Web of Science ®Google Scholar
• Sato T, Takeuchi M, Karasawa Y, Enoki T, Ito M. Intraocular inflammatory cytokines in patients with neovascular age-related macular degeneration before and after initiation of intravitreal injection of anti-VEGF inhibitor. Sci Rep. 2018;8(1):1098. doi:10.1038/s41598-018-19594-6.
   PubMed Web of Science ®Google Scholar
• Dunaief JL, Dentchev T, Ying G, Milam AH. The role of apoptosis in age-related macular degeneration. Arch Ophthalmol. 2002;120(11):1435–42. doi:10.1001/archopht.120.11.1435.
   PubMedGoogle Scholar
• Hanus J, Anderson C, Wang S. RPE necroptosis in response to oxidative stress and in AMD. Ageing Res Rev. 2015;24:286–98. doi:10.1016/j.arr.2015.09.002.
   PubMed Web of Science ®Google Scholar
• Klein R, Klein BEK, Tomany SC, Meuer SM, Huang G-H. Ten-year incidence and progression of age-related maculopathy: the Beaver Dam eye study. Ophthalmology. 2002;109(10):1767–79. doi:10.1016/S0161-6420(02)01146-6.
   PubMed Web of Science ®Google Scholar
• Marin-Castano ME. Cigarette smoking and hypertension two risk factors for age- related macular degeneration. In: Lo GG, editor. Age-related macular degeneration - etiology, diagnosis and management - a glance at the future. Rijeka (Croatia): InTech; 2013. p. 39–101. doi:10.5772/53958.
   Google Scholar
• Bergen AA, Arya S, Koster C, Pilgrim MG, Wiatrek-Moumoulidis D, van der Spek PJ, Hauck SM, Boon CJF, Emri E, Stewart AJ, et al. On the origin of proteins in human drusen: the meet, greet and stick hypothesis. Prog Retin Eye Res. 2018. doi:10.1016/j.preteyeres.2018.12.003.
   Web of Science ®Google Scholar
• Yanai R, Chen S, Uchi S-H, Nanri T, Connor KM, Kimura K. Attenuation of choroidal neovascularization by dietary intake of ω-3 long-chain polyunsaturated fatty acids and lutein in mice. PLoS One. 2018;13(4):e0196037–e0196037. doi:10.1371/journal.pone.0196037.
   PubMed Web of Science ®Google Scholar
• Colijn JM, Den Hollander AI, Demirkan A, Cougnard-Grégoire A, Verzijden T, Kersten E, Meester-Smoor MA, Merle BMJ, Papageorgiou G, Ahmad S, et al. Increased high-density lipoprotein levels associated with age-related macular degeneration: evidence from the EYE-RISK and European eye epidemiology consortia. Ophthalmology. 2018. doi:10.1016/j.ophtha.2018.09.045.
   Web of Science ®Google Scholar
• Fritsche LG, Igl W, Bailey JNC, Grassmann F, Sengupta S, Bragg-Gresham JL, Burdon KP, Hebbring SJ, Wen C, Gorski M, et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 2016;48(2):134–43. doi:10.1038/ng.3448.
   PubMed Web of Science ®Google Scholar
• Tsai ASH, Cheung N, Gan ATL, Jaffe GJ, Sivaprasad S, Wong TY, Cheung CMG. Retinal angiomatous proliferation. Surv Ophthalmol. 2017;62(4):462–92. doi:10.1016/j.survophthal.2017.01.008.
   PubMed Web of Science ®Google Scholar
• Killingsworth MC. Angiogenesis in early choroidal neovascularization secondary to age-related macular degeneration. Graefe’s Arch Clin Exp Ophthalmol. 1995;233(6):313–23. doi:10.1007/BF00200479.
   PubMed Web of Science ®Google Scholar
• Yuzawa M, Fujita K, Wittrup-Jensen KU, Norenberg C, Zeitz O, Adachi K, Wang ECY, Heier J, Kaiser P, Chong V, et al. Improvement in vision-related function with intravitreal aflibercept. Ophthalmology. 2015;122(3):571–78. doi:10.1016/j.ophtha.2014.09.024.
   PubMed Web of Science ®Google Scholar
• Gemenetzi M, Lotery AJ, Patel PJ. Risk of geographic atrophy in age-related macular degeneration patients treated with intravitreal anti-VEGF agents. Eye (Lond). 2017;31(1):1–9. doi:10.1038/eye.2016.208.
   Google Scholar
• Kuroda Y, Yamashiro K, Ooto S, Tamura H, Oishi A, Nakanishi H, Miyata M, Hata M, Takahashi A, Wakazono T, et al. Macular atrophy and macular morphology in aflibercept-treated neovascular age-related macular degeneration. Retina. 2018;38(9):1743–1750.
   Google Scholar
• Chew EY, Clemons TE, Agrón E, Sperduto RD, SanGiovanni JP, Kurinij N, Davis MD. Long-term effects of vitamins C and E, β-carotene, and zinc on age-related macular degeneration. Ophthalmology. 2013;120(8):1604–1611.e4. doi:10.1016/j.ophtha.2013.01.021.
   PubMed Web of Science ®Google Scholar
• Yaspan BL, Williams DF, Holz FG, Regillo CD, Li Z, Dressen A, van Lookeren Campagne M, Le KN, Graham RR, Beres T, et al. Targeting factor D of the alternative complement pathway reduces geographic atrophy progression secondary to age-related macular degeneration. Sci Transl Med. 2017;9(395):eaaf1443. doi:10.1126/scitranslmed.aaf1443.
   PubMed Web of Science ®Google Scholar
• Augustin AJ, Diehm C, Grieger F, Bentz J. Alprostadil infusion in patients with dry age related macular degeneration: a randomized controlled clinical trial. Expert Opin Investig Drugs. 2013;22(7):803–12. doi:10.1517/13543784.2013.794782.
   PubMed Web of Science ®Google Scholar
• Da Cruz L, Fynes K, Georgiadis O, Kerby J, Luo YH, Ahmado A, Vernon A, Daniels JT, Nommiste B, Hasan SM, et al. Phase 1 clinical study of an embryonic stem cell–derived retinal pigment epithelium patch in age-related macular degeneration. Nat Biotechnol. 2018;36:328. doi:10.1038/nbt.4046.
   PubMed Web of Science ®Google Scholar
• Ambati J, Fowler B. Mechanisms of age-related macular degeneration. Neuron. 2012;75(1):26–39. doi:10.1016/j.neuron.2012.06.018.Mechanisms.
   PubMed Web of Science ®Google Scholar
• Rizzolo LJ, Peng S, Luo Y, Xiao W. Integration of tight junctions and claudins with the barrier functions of the retinal pigment epithelium. Prog Retin Eye Res. 2011;30(5):296–323. doi:10.1016/j.preteyeres.2011.06.002.
   PubMed Web of Science ®Google Scholar
• Huang J, Possin DE, Saari JC. Localizations of visual cycle components in retinal pigment epithelium. Mol Vis. 2009;15:223–34.
   PubMed Web of Science ®Google Scholar
• Kevany B, Palczewski K. Phagocytosis of retinal rod and cone photoreceptors. Physiology (Bethesda). 2010;25(1):8–15. doi:10.1152/physiol.00038.2009.Phagocytosis.
   Google Scholar
• Kelly M, Widjaja-Adhi MAK, Palczewski G, von Lintig J. Transport of vitamin A across blood–tissue barriers is facilitated by STRA6. FASEB J. 2016;30(8):2985–95. doi:10.1096/fj.201600446R.
   PubMed Web of Science ®Google Scholar
• Ban Y, Rizzolo LJ. Regulation of glucose transporters during development of the retinal pigment epithelium. Dev Brain Res. 2000;121(1):89–95. doi:10.1016/S0165-3806(00)00028-6.
   PubMedGoogle Scholar
• Strauß O. Transport mechanisms of the retinal pigment epithelium to maintain of visual function. Heat Mass Transf. 2014;50(3):303–13. doi:10.1007/s00231-013-1267-z.
   Web of Science ®Google Scholar
• Saint-Geniez M, Kurihara T, Sekiyama E, Maldonado AE, D’Amore PA. An essential role for RPE-derived soluble VEGF in the maintenance of the choriocapillaris. Proc Natl Acad Sci U S A. 2009;106(44):18751–56. doi:10.1073/pnas.0905010106.
   PubMed Web of Science ®Google Scholar
• Kamba T, Tam BYY, Hashizume H, Haskell A, Sennino B, Mancuso MR, Norberg SM, O’Brien SM, Davis RB, Gowen LC, et al. VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol. 2006;290(2):H560–H576. doi:10.1152/ajpheart.00133.2005.
   PubMed Web of Science ®Google Scholar
• Blaauwgeers HG, Holtkamp GM, Rutten H, Witmer AN, Koolwijk P, Partanen TA, Alitalo K, Kroon ME, Kijlstra A, van Hinsbergh VW, et al. Polarized vascular endothelial growth factor secretion by human retinal pigment epithelium and localization of vascular endothelial growth factor receptors on the inner choriocapillaris. Evidence for atrophic paracrine relation. Am J Pathol. 1999;155(2):421–28. doi:10.1016/S0002-9440(10)65138-3.
   PubMed Web of Science ®Google Scholar
• Julien S, Kreppel F, Beck S, Heiduschka P, Brito V, Schnichels S, Kochanek S, Schraermeyer U. A reproducible and quantifiable model of choroidal neovascularization induced by VEGF A(165) after subretinal adenoviral gene transfer in the rabbit. Mol Vis. 2008;14:1358–71.
   PubMed Web of Science ®Google Scholar
• Chou H-D, Wu W-C, Wang N-K, Chuang L-H, Chen K-J, Lai -C-C. Short-term efficacy of intravitreal Aflibercept injections for retinal angiomatous proliferation. BMC Ophthalmol. 2017;17(1):104. doi:10.1186/s12886-017-0497-0.
   PubMed Web of Science ®Google Scholar
• Kim I, Ryan AM, Rohan R, Amano S, Agular S, Miller JW, Adamis AP. Constitutive expression of VEGF, VEGFR-1, and VEGFR-2 in normal eyes. Invest Ophthalmol Vis Sci. 1999;40:2115–21.
   PubMed Web of Science ®Google Scholar
• Zhao J, Geng YU, Hua H, Cun B, Chen Q, Xi X, Yang L, Li YAN. Fenofibrate inhibits the expression of VEGFC and VEGFR-3 in retinal pigmental epithelial cells exposed to hypoxia. Exp Ther Med. 2015;10(4):1404–12. doi:10.3892/etm.2015.2697.
   PubMed Web of Science ®Google Scholar
• Lim JI, Spee C, Hangai M, Rocha J, Ying HS, Ryan SJ, Hinton DR. Neuropilin-1 expression by endothelial cells and retinal pigment epithelial cells in choroidal neovascular membranes. Am J Ophthalmol. 2005;140(6):1044–1050.e1. doi:10.1016/j.ajo.2005.07.021.
   PubMed Web of Science ®Google Scholar
• Klettner A, Roider J. Constitutive and oxidative-stress-induced expression of VEGF in the RPE are differently regulated by different Mitogen-activated protein kinases. Graefe’s Arch Clin Exp Ophthalmol. 2009;247(11):1487–92. doi:10.1007/s00417-009-1139-x.
   PubMed Web of Science ®Google Scholar
• Cachafeiro M, Bemelmans A-P, Samardzija M, Afanasieva T, Pournaras J-A, Grimm C, Kostic C, Philippe S, Wenzel A, Arsenijevic Y. Hyperactivation of retina by light in mice leads to photoreceptor cell death mediated by VEGF and retinal pigment epithelium permeability. Cell Death Dis. 2013;4(e781):1–11. doi:10.1038/cddis.2013.303.
   Web of Science ®Google Scholar
• Zhang L, Liu H, Peng YM, Dai -Y-Y, Liu F-Y. Vascular endothelial growth factor increases GEnC permeability by affecting the distributions of occludin, ZO-1 and tight juction assembly. Eur Rev Med Pharmacol Sci. 2015;19:2621–27.
   PubMed Web of Science ®Google Scholar
• Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci U S A. 1991;88(20):9267–71. doi:10.1073/pnas.88.20.9267.
   PubMed Web of Science ®Google Scholar
• Rätsep MT, Carmeliet P, Adams MA, Croy BA. Impact of placental growth factor deficiency on early mouse implant site angiogenesis. Placenta. 2014;35(9):772–75. doi:10.1016/j.placenta.2014.07.006.
   PubMed Web of Science ®Google Scholar
• Cao Y, Ji W-R, Qi P, Rosin Å, Cao Y. Placenta growth factor: identification and characterization of a novel isoform generated by RNA alternative splicing. Biochem Biophys Res Commun. 1997;235(3):493–98. doi:10.1006/bbrc.1997.6813.
   PubMed Web of Science ®Google Scholar
• Yang W, Ahn H, Hinrichs M, Torry RJ, Torry DS. Evidence of a novel isoform of placenta growth factor (PlGF-4) expressed in human trophoblast and endothelial cells. J Reprod Immunol. 2003;60(1):53–60. doi:10.1016/S0165-0378(03)00082-2.
   PubMed Web of Science ®Google Scholar
• Maglione D, Guerriero V, Viglietto G, Ferraro MG, Aprelikova O, Alitalo K, Del Vecchio S, Lei KJ, Chou JY, Persico MG. Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PlGF), are transcribed from a single gene of chromosome 14. Oncogene. 1993;8:925–31.
   PubMed Web of Science ®Google Scholar
• Sawano A, Takahashi T, Yamaguchi S, Aonuma M, Shibuya M. Flt-1 but not KDR/Flk-1 tyrosine kinase is a receptor for placenta growth factor, which is related to vascular endothelial growth factor. Cell Growth Differ. 1996;7:213–21.
   PubMedGoogle Scholar
• Migdal M, Huppertz B, Tessler S, Comforti A, Shibuya M, Reich R, Baumann H, Neufeld G. Neuropilin-1 is a placenta growth factor-2 receptor. J Biol Chem. 1998;273(35):22272–78. doi:10.1074/jbc.273.35.22272.
   PubMed Web of Science ®Google Scholar
• Tjwa M, Luttun A, Autiero M, Carmeliet P. VEGF and PIGF: two pleiotropic growth factors with distinct roles in development and homeostasis. Cell Tissue Res. 2003;314(1):5–14. doi:10.1007/s00441-003-0776-3.
   PubMed Web of Science ®Google Scholar
• Autiero M, Waltenberger J, Communi D, Kranz A, Moons L, Lambrechts D, Kroll J, Plaisance S, De Mol M, Bono F, et al. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med. 2003;9(7):936–43. doi:10.1038/nm884.
   PubMed Web of Science ®Google Scholar
• Clegg LE, Mac Gabhann F. A computational analysis of in vivo VEGFR activation by multiple co-expressed ligands. PLOS Comput Biol. 2017;13(3):e1005445. doi:10.1371/journal.pcbi.1005731.
   PubMed Web of Science ®Google Scholar
• Eriksson A, Cao R, Pawliuk R, Berg SM, Tsang M, Zhou D, Fleet C, Tritsaris K, Dissing S, Leboulch P, et al. Placenta growth factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PlGF-1/VEGF heterodimers. Cancer Cell. 2002;1(1):99–108. doi:10.1016/S1535-6108(02)00028-4.
   PubMed Web of Science ®Google Scholar
• Apicella I, Cicatiello V, Acampora D, Tarallo V, De Falco S. Full functional knockout of placental growth factor by knockin with an inactive variant able to heterodimerize with VEGF-A. Cell Rep. 2018;23(12):3635–46. doi:10.1016/j.celrep.2018.05.067.
   PubMed Web of Science ®Google Scholar
• Snuderl M, Batista A, Kirkpatrick ND, De Almodovar CR, Riedemann L, Walsh EC, Anolik R, Huang Y, Martin JD, Kamoun W, et al. Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell. 2013;152(5):1065–76. doi:10.1016/j.cell.2013.01.036.
   PubMed Web of Science ®Google Scholar
• Gigante B, Tarsitano M, Cimini V, De Falco S, Persico MG. Placenta growth factor is not required for exercise-induced angiogenesis. Angiogenesis. 2004;7(3):277–84. doi:10.1007/s10456-004-4179-1.
   PubMedGoogle Scholar
• Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, Wu Y, Bono F, Devy L, Beck H, et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med. 2001;7(5):575–83. doi:10.1038/87904.
   PubMed Web of Science ®Google Scholar
• Gigante B, Morlino G, Gentile MT, Persico MG, De Falco S. Plgf-/-eNos-/- mice show defective angiogenesis associated with increased oxidative stress in response to tissue ischemia. FASEB J Off Publ Fed Am Soc Exp Biol. 2006;20(7):970–72. doi:10.1096/fj.05-4481fje.
   PubMed Web of Science ®Google Scholar
• Freitas-Andrade M, Carmeliet P, Charlebois C, Stanimirovic DB, Moreno MJ. PlGF knockout delays brain vessel growth and maturation upon systemic hypoxic challenge. J Cereb Blood Flow Metab. 2012;32(4):663–75. doi:10.1038/jcbfm.2011.167.
   PubMed Web of Science ®Google Scholar
• Van Bergen T, Hu -T-T, Etienne I, Reyns GE, Moons L, Feyen JHM. Neutralization of placental growth factor as a novel treatment option in diabetic retinopathy. Exp Eye Res. 2017;165:136–50. doi:10.1016/j.exer.2017.09.012.
   PubMed Web of Science ®Google Scholar
• Al Kahtani E, Xu Z, Al Rashaed S, Wu L, Mahale A, Tian J, Abboud EB, Ghazi NG, Kozak I, Gupta V, et al. Vitreous levels of placental growth factor correlate with activity of proliferative diabetic retinopathy and are not influenced by bevacizumab treatment. Eye (Lond). 2017;31(4):529–36. doi:10.1038/eye.2016.246.
   Google Scholar
• Rakic J-M, Lambert V, Devy L, Luttun A, Carmeliet P, Claes C, Nguyen L, Foidart J-M, Noel A, Munaut C. Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization. Invest Ophthalmol Vis Sci. 2003;44(7):3186–93. doi:10.1167/iovs.02-1092.
   PubMed Web of Science ®Google Scholar
• Huang H, Parlier R, Shen J, Lutty GA, Vinores SA. VEGF receptor blockade markedly reduces retinal microglia/macrophage infiltration into laser-induced CNV. PLoS One. 2013;8(8):e71808. doi:10.1371/journal.pone.0071808.
   PubMed Web of Science ®Google Scholar
• Ishida S, Shinoda K, Kawashima S, Oguchi Y, Okada Y, Ikeda E. Coexpression of VEGF receptors VEGF-R2 and neuropilin-1 in proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci. 2000;41:1649–56.
   PubMed Web of Science ®Google Scholar
• Cao R, Xue Y, Hedlund E-M, Zhong Z, Tritsaris K, Tondelli B, Lucchini F, Zhu Z, Dissing S, Cao Y. VEGFR1–mediated pericyte ablation links VEGF and PlGF to cancer-associated retinopathy. Proc Natl Acad Sci. 2010;107(2):856 LP–861. doi:10.1073/pnas.0911661107.
   Web of Science ®Google Scholar
• Van Bergen T, Etienne I, Cunningham F, Moons L, Schlingemann RO, Feyen JHM, Stitt AW. The role of placental growth factor (PlGF) and its receptor system in retinal vascular diseases. Prog Retin Eye Res. 2018 Oct. doi:10.1016/j.preteyeres.2018.10.006.
   PubMed Web of Science ®Google Scholar
• Nourinia R, Soheili Z-S, Ahmadieh H, Akrami H, Rezaei Kanavi M, Samiei S. Knockdown of the placental growth factor gene inhibits laser induced choroidal neovascularization in a murine model. J Ophthalmic Vis Res. 2013;8:4–8.
   PubMedGoogle Scholar
• Van de Veire S, Stalmans I, Heindryckx F, Oura H, Tijeras-Raballand A, Schmidt T, Loges S, Albrecht I, Jonckx B, Vinckier S, et al. Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease. Cell. 2010;141(1):178–90. doi:10.1016/j.cell.2010.02.039.
   PubMed Web of Science ®Google Scholar
• Miyamoto N, de Kozak Y, Jeanny JC, Glotin A, Mascarelli F, Massin P, BenEzra D, Behar-Cohen F. Placental growth factor-1 and epithelial haemato-retinal barrier breakdown: potential implication in the pathogenesis of diabetic retinopathy. Diabetologia. 2007;50(2):461–70. doi:10.1007/s00125-006-0539-2.
   PubMed Web of Science ®Google Scholar
• Kowalczuk L, Touchard E, Omri S, Jonet L, Klein C, Valamanes F, Berdugo M, Bigey P, Massin P, Jeanny JC, et al. Placental growth factor contributes to micro-vascular abnormalization and blood-retinal barrier breakdown in diabetic retinopathy. PLoS One. 2011;6(3):e17462. doi:10.1371/journal.pone.0017462.
   PubMed Web of Science ®Google Scholar
• Huang H, He J, Johnson D, Wei Y, Liu Y, Wang S, Lutty GA, Duh EJ, Semba RD. Deletion of placental growth factor prevents diabetic retinopathy and is associated with akt activation and HIF1α-VEGF pathway inhibition. Diabetes. 2015;64(1):200–12. doi:10.2337/db14-0016.
   PubMed Web of Science ®Google Scholar
• Saddala MS, Lennikov A, Grab DJ, Liu G-S, Tang S, Huang H. Proteomics reveals ablation of PlGF increases antioxidant and neuroprotective proteins in the diabetic mouse retina. Sci Rep. 2018;8(1):16728. doi:10.1038/s41598-018-34955-x.
   PubMed Web of Science ®Google Scholar
• Yuzawa M, Fujita K, Wittrup-Jensen KU, Norenberg C, Zeitz O, Adachi K, Wang ECY, Heier J, Kaiser P, Chong V, et al. Improvement in vision-related function with intravitreal aflibercept: data from phase 3 studies in wet age-related macular degeneration. Ophthalmology. 2015;122(3):571–78. doi:10.1016/j.ophtha.2014.09.024.
   PubMed Web of Science ®Google Scholar
• Gillies MC, Nguyen V, Daien V, Arnold JJ, Morlet N, Barthelmes D. Twelve-month outcomes of ranibizumab vs. aflibercept for neovascular age-related macular degeneration: data from an observational study. Ophthalmology. 2016;123(12):2545–53. doi:10.1016/j.ophtha.2016.08.016.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Chioreso C, Schweizer ML, Abràmoff MD. Effects of aflibercept for neovascular age-related macular degeneration: a systematic review and meta-analysis of observational comparative studies. Invest Ophthalmol Vis Sci. 2017;58(13):5616–27. doi:10.1167/iovs.17-22471.
   PubMed Web of Science ®Google Scholar
• Ashraf M, Souka AAR. Aflibercept in age-related macular degeneration: evaluating its role as a primary therapeutic option. Eye (Lond). 2017;31(11):1523–36. doi:10.1038/eye.2017.81.
   PubMed Web of Science ®Google Scholar
• Rasmussen A, Sander B, Larsen M, Brandi S, Fuchs J, Hansen LH, Lund-Andersen H. Neovascular age-related macular degeneration treated with ranibizumab or aflibercept in the same large clinical setting: visual outcome and number of injections. Acta Ophthalmol. 2017;95(2):128–32. doi:10.1111/aos.13233.
   PubMed Web of Science ®Google Scholar
• Waldstein SM, Simader C, Staurenghi G, Chong NV, Mitchell P, Jaffe GJ, Lu C, Katz TA, Schmidt-Erfurth U. Morphology and visual acuity in aflibercept and ranibizumab therapy for neovascular age-related macular degeneration in the VIEW trials. Ophthalmology. 2016;123(7):1521–29. doi:10.1016/j.ophtha.2016.03.037.
   PubMed Web of Science ®Google Scholar
• Pongsachareonnont P, Mak MYK, Hurst CP, Lam W-C. Neovascular age-related macular degeneration: intraocular inflammatory cytokines in the poor responder to ranibizumab treatment. Clin Ophthalmol. 2018;12:1877–85. doi:10.2147/OPTH.S171636.
   PubMed Web of Science ®Google Scholar
• Hou -H-H, Cheng S-L, Chung K-P, Kuo MY-P, Yeh -C-C, Chang B-E, Lu -H-H, Wang H-C, Yu C-J. Elastase induces lung epithelial cell autophagy through placental growth factor: A new insight of emphysema pathogenesis. Autophagy. 2014;10(9):1509–21. doi:10.4161/auto.29190.
   PubMed Web of Science ®Google Scholar
• Wu D, Yuan Y, Lin Z, Lai T, Chen M, Li W, Lv Q, Yuan B, Li D, Wu B. Cigarette smoke extract induces placental growth factor release from human bronchial epithelial cells via ROS/MAPK (ERK-1/2)/Egr-1 axis. Int J Chron Obstruct Pulmon Dis. 2016;11:3031–42. doi:10.2147/COPD.S120849.
   PubMed Web of Science ®Google Scholar
• Zhang L, Zhao S, Yuan L, Wu H, Jiang H, Luo G, Zhao S. Knockdown of placental growth factor (PLGF) mitigates hyperoxia-induced acute lung injury in neonatal rats: suppressive effects on NFκB signaling pathway. Int Immunopharmacol. 2016;38:167–74. doi:10.1016/j.intimp.2016.05.028.
   PubMed Web of Science ®Google Scholar
• Zhang L, Zhao S, Yuan L, Wu H, Jiang H, Luo G. Placental growth factor triggers epithelial-to-mesenchymal transition-like changes in rat type II alveolar epithelial cells: activation of nuclear factor κB signalling pathway. Basic Clin Pharmacol Toxicol. 2016;119(5):498–504. doi:10.1111/bcpt.12616.
   PubMed Web of Science ®Google Scholar
• Huang W, Zhu S, Liu Q, Li C, Li L. Placenta growth factor promotes migration through regulating epithelial-mesenchymal transition-related protein expression in cervical cancer. Int J Clin Exp Pathol. 2014;7:8506–19.
   PubMed Web of Science ®Google Scholar
• McLeod DS, Grebe R, Bhutto I, Merges C, Baba T, Lutty GA. Relationship between RPE and choriocapillaris in age-related macular degeneration. Investig Opthalmology Vis Sci. 2009;50(10):4982–91. doi:10.1167/iovs.09-3639.
   PubMed Web of Science ®Google Scholar
• Mullins RF, Johnson MN, Faidley EA, Skeie JM, Huang J. Choriocapillaris vascular dropout related to density of drusen in human eyes with early age-related macular degeneration. Investig Opthalmology Vis Sci. 2011;52(3):1606–12. doi:10.1167/iovs.10-6476.
   PubMed Web of Science ®Google Scholar
• Korte GE, Reppucci V, Henkind P. RPE destruction causes choriocapillary atrophy. Invest Ophthalmol Vis Sci. 1984;25:1135–45.
   PubMed Web of Science ®Google Scholar
• Hollborn M, Tenckhoff S, Seifert M, Köhler S, Wiedemann P, Bringmann A, Kohen L. Human retinal epithelium produces and responds to placenta growth factor. Graefe’s Arch Clin Exp Ophthalmol. 2006;244(6):732–41. doi:10.1007/s00417-005-0154-9.
   PubMed Web of Science ®Google Scholar
• Izawa H, Inoue Y, Ohno Y, Ojino K, Tsuruma K, Shimazawa M, Hara H. Protective effects of antiplacental growth factor antibody against light-induced retinal damage in mice. Investig Ophthalmol Vis Sci. 2015;56(11):6914–24. doi:10.1167/iovs.15-16748.
   PubMed Web of Science ®Google Scholar
• Narimatsu T, Ozawa Y, Miyake S, Kubota S, Hirasawa M, Nagai N, Shimmura S, Tsubota K. Disruption of cell-cell junctions and induction of pathological cytokines in the retinal pigment epithelium of light-exposed mice. Investig Opthalmology Vis Sci. 2013;54(7):4555–62. doi:10.1167/iovs.12-11572.
   PubMed Web of Science ®Google Scholar
• Chen J, Ye L, Zhang L, Jiang WG. Placenta growth factor, PLGF, influences the motility of lung cancer cells, the role of Rho associated kinase, Rock1. J Cell Biochem. 2008;105(1):313–20. doi:10.1002/jcb.21831.
   PubMed Web of Science ®Google Scholar
• Kuse Y, Takahashi K, Inoue Y, Izawa H, Nakamura S, Shimazawa M, Hara H. Intravitreal aflibercept protects photoreceptors of mice against excessive light exposure. J Pharmacol Sci. 2018;137(4):407–11. doi:10.1016/j.jphs.2018.07.010.
   PubMed Web of Science ®Google Scholar
• Clauss M, Weich H, Breier G, Knies U, Röckl W, Waltenberger J, Risau W. The vascular endothelial growth factor receptor Flt-1 mediates biological activities: implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J Biol Chem. 1996;271(30):17629–34. doi:10.1074/jbc.271.30.17629.
   PubMed Web of Science ®Google Scholar
• Selvaraj SK, Giri RK, Perelman N, Johnson C, Malik P, Kalra VK. Mechanism of monocyte activation and expression of proinflammatory cytochemokines by placenta growth factor. Blood. 2003;102(4):1515 LP–1524. doi:10.1182/blood-2002-11-3423.
   Web of Science ®Google Scholar
• Khurana R, Moons L, Shafi S, Luttun A, Collen D, Martin JF, Carmeliet P, Zachary IC. Placental growth factor promotes atherosclerotic intimal thickening and macrophage accumulation. Circulation. 2005;111(21):2828 LP–2836. doi:10.1161/CIRCULATIONAHA.104.495887.
   Web of Science ®Google Scholar
• Yoo S-A, Yoon H-J, Kim H-S, Chae C-B, De Falco S, Cho C-S, Kim W-U. Role of placenta growth factor and its receptor flt-1 in rheumatoid inflammation: A link between angiogenesis and inflammation. Arthritis Rheum. 2009;60(2):345–54. doi:10.1002/art.24289.
   PubMed Web of Science ®Google Scholar
• Eiymo Mwa Mpollo M-S, Brandt EB, Shanmukhappa SK, Arumugam PI, Tiwari S, Loberg A, Pillis D, Rizvi T, Lindsey M, Jonck B, et al. Placenta growth factor augments airway hyperresponsiveness via leukotrienes and IL-13. J Clin Invest. 2016;126(2):571–84. doi:10.1172/JCI77250.
   PubMed Web of Science ®Google Scholar
• Li X, Yao Q, Liu H, Jin Q, Xu B, Zhang S, Tu C. Placental growth factor silencing ameliorates liver fibrosis and angiogenesis and inhibits activation of hepatic stellate cells in a murine model of chronic liver disease. J Cell Mol Med. 2017;21(10):2370–85. doi:10.1111/jcmm.13158.
   PubMed Web of Science ®Google Scholar
• Kauppinen A, Paterno JJ, Blasiak J, Salminen A, Kaarniranta K. Inflammation and its role in age-related macular degeneration. Cell Mol Life Sci. 2016;73:1765–86. doi:10.1007/s00018-016-2147-8.
   PubMed Web of Science ®Google Scholar
• Mullins RF, Schoo DP, Sohn EH, Flamme-Wiese MJ, Workamelahu G, Johnston RM, Wang K, Tucker BA, Stone EM. The membrane attack complex in aging human choriocapillaris. Am J Pathol. 2014;184(11):3142–53. doi:10.1016/j.ajpath.2014.07.017.
   PubMed Web of Science ®Google Scholar
• Thurman JM, Renner B, Kunchithapautham K, Ferreira VP, Pangburn MK, Ablonczy Z, Tomlinson S, Holers VM, Rohrer B. Oxidative stress renders retinal pigment epithelial cells susceptible to complement-mediated injury. J Biol Chem. 2009;284(25):16939–47. doi:10.1074/jbc.M808166200.
   PubMed Web of Science ®Google Scholar
• Kunchithapautham K, Atkinson C, Rohrer B. Smoke exposure causes endoplasmic reticulum stress and lipid accumulation in retinal pigment epithelium through oxidative stress and complement activation. J Biol Chem. 2014;289(21):14534–46. doi:10.1074/jbc.M114.564674.
   PubMed Web of Science ®Google Scholar
• Lin T, Walker GB, Kurji K, Fang E, Law G, Prasad SS, Kojic L, Cao S, White V, Cui JZ, et al. Parainflammation associated with advanced glycation endproduct stimulation of RPE in vitro: implications for age-related degenerative diseases of the eye. Cytokine. 2013;62(3):369–81. doi:10.1016/j.cyto.2013.03.027.
   PubMed Web of Science ®Google Scholar
• Luttun A, Tjwa M, Moons L, Wu Y, Angelillo-Scherrer A, Liao F, Nagy JA, Hooper A, Priller J, De Klerck B, et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med. 2002;8(8):831–40. doi:10.1038/nm731.
   PubMed Web of Science ®Google Scholar
• Balser C, Wolf A, Herb M, Langmann T. Co-inhibition of PGF and VEGF blocks their expression in mononuclear phagocytes and limits neovascularization and leakage in the murine retina. J Neuroinflammation. 2019;16(1):1–12. doi:10.1186/s12974-019-1419-2.
   PubMed Web of Science ®Google Scholar
• Ma W, Zhao L, Wong WT. Microglia in the outer retina and their relevance to pathogenesis of age-related macular degeneration. Adv Exp Med Biol. 2012;723:37–42. doi:10.1007/978-1-4614-0631-0_6.
   PubMed Web of Science ®Google Scholar
• Zhang S, Yu N, Zhang R, Zhang S, Wu J. Interleukin-17A induces IL-1β secretion from RPE cells via the NLRP3 InflammasomeIL-17A induces IL-1β secretion from RPE cells. Invest Ophthalmol Vis Sci. 2016;57(2):312–19. doi:10.1167/iovs.15-17578.
   PubMed Web of Science ®Google Scholar
• Ding X, Gu R, Zhang M, Ren H, Shu Q, Xu G, Wu H. Microglia enhanced the angiogenesis, migration and proliferation of co-cultured RMECs. BMC Ophthalmol. 2018;18(1):249. doi:10.1186/s12886-018-0886-z.
   PubMed Web of Science ®Google Scholar
• Keir LS, Firth R, Aponik L, Feitelberg D, Sakimoto S, Aguilar E, Gi W, Richards A, Usui Y, Satchell SC, et al. VEGF regulates local inhibitory complement proteins in the eye and kidney. J Clin Invest. 2017;127(1):199–214. doi:10.1172/JCI86418.
   PubMed Web of Science ®Google Scholar
• Indraccolo S. Vascular endothelial growth factor blockade elicits a stable metabolic shift in tumor cells: therapeutic implications. Mol Cell Oncol. 2016;3(2):e1008307. doi:10.1080/23723556.2015.1008307.
   PubMed Web of Science ®Google Scholar
• Wu LE, Meoli CC, Mangiafico SP, Fazakerley DJ, Cogger VC, Mohamad M, Pant H, Kang M-J, Powter E, Burchfield JG, et al. Systemic VEGF-A neutralization ameliorates diet-induced metabolic dysfunction. Diabetes. 2014;63(8):2656–67. doi:10.2337/db13-1665.
   PubMed Web of Science ®Google Scholar
• Treps L, Conradi L-C, Harjes U, Carmeliet P. Manipulating angiogenesis by targeting endothelial metabolism: hitting the engine rather than the drivers—a new perspective? Ishikawa Y, editor. Pharmacol Rev. 2016;68(3):872LP–887. doi:10.1124/pr.116.012492.
   Web of Science ®Google Scholar
• Domigan CK, Warren CM, Antanesian V, Happel K, Ziyad S, Lee S, Krall A, Duan L, Torres-Collado AX, Castellani LW, et al. Autocrine VEGF maintains endothelial survival through regulation of metabolism and autophagy. J Cell Sci. 2015;128(12):2236–48. doi:10.1242/jcs.163774.
   PubMed Web of Science ®Google Scholar
• Vallée A, Lecarpentier Y, Guillevin R, Vallée J-N. Aerobic glycolysis hypothesis through WNT/beta-catenin pathway in exudative age-related macular degeneration. J Mol Neurosci. 2017;62(3):368–79. doi:10.1007/s12031-017-0947-4.
   PubMed Web of Science ®Google Scholar
• Parra-Bonilla G, Alvarez DF, Al-Mehdi A-B, Alexeyev M, Stevens T. Critical role for lactate dehydrogenase A in aerobic glycolysis that sustains pulmonary microvascular endothelial cell proliferation. Am J Physiol Lung Cell Mol Physiol. 2010;299(4):L513–L522. doi:10.1152/ajplung.00274.2009.
   PubMed Web of Science ®Google Scholar
• Kurihara T, Westenskow PD, Gantner ML, Usui Y, Schultz A, Bravo S, Aguilar E, Wittgrove C, Friedlander MSH, Paris LP, et al. Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration. Elife. 2016;5(e14319):1–22. doi:10.7554/eLife.14319.
   Web of Science ®Google Scholar
• Xu B, Chen Q, Yin X, Chen W, Li X, Ju R. VEGFR2 regulates energy metabolism and cell survival in retinal pigment epithelium cells. Invest Ophthalmol Vis Sci. 2018;59(9):4031. doi:10.1167/iovs.17-23678.
   PubMed Web of Science ®Google Scholar
• Zhao C, Yasumura D, Li X, Matthes M, Lloyd M, Nielsen G, Ahern K, Snyder M, Bok D, Dunaief JL, et al. mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice. J Clin Invest. 2011;121(1):369–83. doi:10.1172/JCI44303.
   PubMed Web of Science ®Google Scholar
• Gilmore AP. Anoikis. Cell Death Differ. 2005;12:1473–77. doi:10.1038/sj.cdd.4401723.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Zhao L, Wang L, Yang X, Zhou A, Wang J. Placental growth factor promotes epithelial-mesenchymal transition-like changes in ARPE-19 cells under hypoxia. Mol Vis. 2018;24:340–52.
   PubMed Web of Science ®Google Scholar
• Curcio CA, Zanzottera EC, Ach T, Balaratnasingam C, Freund KB. Activated retinal pigment epithelium, an optical coherence tomography biomarker for progression in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2017;58(6):BIO211–BIO226. doi:10.1167/iovs.17-21872.
   PubMed Web of Science ®Google Scholar
• Hyttinen JMT, Błasiak J, Niittykoski M, Kinnunen K, Kauppinen A, Salminen A, Kaarniranta K. DNA damage response and autophagy in the degeneration of retinal pigment epithelial cells—implications for age-related macular degeneration (AMD). Ageing Res Rev. 2017;36:64–77. doi:10.1016/j.arr.2017.03.006.
   PubMed Web of Science ®Google Scholar