Plazenta-Wachstumsfaktor (PlGF) und retinale Gefäßerkrankungen – experimentelle und klinische Datenlage

Zusammenfassung

Die pathologische Angiogenese ist ein wesentliches Kennzeichen von Erkrankungen wie Krebs und retinalen Gefäßerkrankungen. Gefäßerkrankungen im Auge, wie diabetische Retinopathie (DR) und neovaskuläre altersabhängige Makuladegeneration (nAMD), sind die Hauptursachen von schwerwiegenden, häufig irreversiblen Sehverschlechterungen. Die besondere Rolle des Wachstumsfaktors VEGF-A bei diesen Erkrankungen gilt als belegt. Daher ist dieser Hauptziel antiangiogener Therapien. Ein weiterer angiogener Faktor, der Plazenta-Wachstumsfaktor (PlGF), rückt erst in letzter Zeit zunehmend in den Fokus klinischer Forschung. Grund dafür ist, dass die Expression von PlGF fast ausschließlich während der embryonalen Entwicklung stattfindet und entsprechend im gesunden Gewebe kaum oder gar nicht vorzufinden ist. Bei pathologischen angiogenen Prozessen jedoch, wie bei retinalen Gefäßerkrankungen, wird PlGF verstärkt exprimiert. Substanzen, welche die Wirkung von PlGF und damit die pathologische Angiogenese inhibieren, ohne gleichzeitig gesundes Gewebe zu beeinflussen, könnten die Therapieoptionen zur Behandlung retinaler Gefäßerkrankungen entscheidend erweitern. Erste klinische Studien aus der Onkologie und präklinische Untersuchungen an Tiermodellen retinaler Gefäßerkrankungen sind bereits publiziert. Ziel dieses Beitrags ist es, eine Übersicht über die Rolle von PlGF bei retinalen Gefäßerkrankungen und die experimentelle Datenlage zusammenzufassen und das mögliche therapeutische Potenzial PlGF-inhibierender Substanzen zu beleuchten.

Abstract

Pathological angiogenesis is a major characteristic of many diseases, such as cancer and retinal vascular disorders. Vascular diseases of the eye, such as diabetic retinopathy (DR) and neo-vascular age-related macular degeneration (nAMD), are the main cause of severe vision loss. The specific role of the cytokine VEGF-A in these pathologies has been proven in many ways. Thus, VEGF-A is still the major target for antiangiogenic therapy. Recently, another angiogenic factor, the placental growth factor (PlGF), has become a focal point for clinical research. This interest is based on the fact that the expression of PlGF is limited to embryonic development and PlGF can hardly be found in healthy tissues. During pathological angiogenetic processes, such as retinal vascular diseases, however, PlGF is increasingly expressed. Substances which inhibit the effect of PlGF and thus pathological angiogenesis, without simultaneously affecting healthy tissues, could significantly extend the therapeutic options for the treatment of retinal vascular diseases. Convincing results have recently been published from clinical trials in oncology, as well as preclinical investigations in animal models of retinal vascular diseases. The aim of this review is to summarise the role of PlGF in retinal vascular diseases and the available experimental data on the therapeutic potential of PlGF inhibitors.

Schlüsselwörter

Angiogenese - antiangiogene Therapie - diabetische Retinopathie - Makuladegeneration - Neovaskularisation - VEGF

Key words

angiogenesis - anti-angiogenic therapy - diabetic retinopathy - macula degeneration - neovascularization - vascular growth factor

• Literatur

• 1 Jonas JB, Jonas RA, Neumaier M et al. Cytokine concentration in aqueous humor of eyes with diabetic macular edema. Retina 2012; 32: 2150-2157
• 2 Katsura Y, Okano T, Matsuno K et al. Erythropoietin is highly elevated in vitreous fluid of patients with proliferative diabetic retinopathy. Diabetes Care 2005; 28: 2252-2254
• 3 Jonas JB, Tao Y, Neumaier M et al. Monocyte chemoattractant protein 1, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 in exudative age-related macular degeneration. Arch Ophthalmol 2010; 128: 1281-1286
• 4 Dvorak HF. Discovery of vascular permeability factor (VPF). Exp Cell Res 2006; 312: 522-526
• 5 Maglione D, Guerriero V, Viglietto G et al. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci USA 1991; 88: 9267-9271
• 6 Luttun A, Tjwa M, Moons L et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 2002; 8: 831-840
• 7 Tchaikovski V, Fellbrich G, Waltenberger J. The molecular basis of VEGFR-1 signal transduction pathways in primary human monocytes. Arterioscler Thromb Vasc Biol 2008; 28: 322-328
• 8 Campochiaro PA. Ocular neovascularization. J Mol Med (Berl) 2013; 91: 311-321
• 9 Scholl S, Kirchhof J, Augustin AJ. Pathophysiology of macular edema. Ophthalmologica 2010; 224 (Suppl. 01) S8-S15
• 10 Fauser S, Engelmann K, Krohne TU et al. Pathogenese der choroidalen Neovaskularisation. Alte Konzepte, neue Fragen. Ophthalmologe 2003; 100: 300-305
• 11 Smith LEH, Wesolowski E, McLellan A et al. Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci 1994; 35: 101-111
• 12 Koch S, Tugues S, Li X et al. Signal transduction by vascular endothelial growth factor receptors. Biochem J 2011; 437: 169-183
• 13 Autiero M, Waltenberger J, Communi D et al. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med 2003; 9: 936-943
• 14 Cao Y. Positive and negative modulation of angiogenesis by VEGFR1 ligands. Sci Signal 2009; 2: re1
• 15 Kendall RL, Thomas KA. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci U S A 1993; 90: 10705-10709
• 16 Kendall RL, Wang G, DiSalvo J et al. Specificity of vascular endothelial cell growth factor receptor ligand binding domains. Biochem Biophys Res Commun 1994; 201: 326-330
• 17 Cao R, Xue Y, Hedlund EM et al. VEGFR1-mediated pericyte ablation links VEGF and PlGF to cancer-associated retinopathy. Proc Natl Acad Sci USA 2010; 107: 856-861
• 18 Domigan CK, Ziyad S, Iruela-Arispe ML. Canonical and noncanonical vascular endothelial growth factor pathways: new developments in biology and signal transduction. Arterioscler Thromb Vasc Biol 2015; 35: 30-39
• 19 Maglione D, Guerriero V, Viglietto G et al. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci USA 1991; 88: 9267-9271
• 20 Dewerchin M, Carmeliet P. PlGF: a multitasking cytokine with disease-restricted activity. Cold Spring Harb Perspect Med 2012; 2 pii: a011056
• 21 Ribatti D. The discovery of the placental growth factor and its role in angiogenesis: a historical review. Angiogenesis 2008; 11: 215-221
• 22 Park JE, Chen HH, Winer J et al. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem 1994; 269: 25646-25654
• 23 De Falco S. The discovery of placenta growth factor and its biological activity. Exp Mol Med 2012; 44: 1-9
• 24 Ziche M, Maglione D, Ribatti D et al. Placenta growth factor-1 is chemotactic, mitogenic, and angiogenic. Lab Invest 1997; 76: 517-531
• 25 Carmeliet P, Moons L, Luttun A 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: 575-583
• 26 Rakic JM, Lambert V, Devy L et al. Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization. Invest Ophthalmol Vis Sci 2003; 44: 3186-3193
• 27 Khaliq A, Foreman D, Ahmed A et al. Increased expression of placenta growth factor in proliferative diabetic retinopathy. Lab Invest 1998; 78: 109-116
• 28 Hollborn M, Tenckhoff S, Seifert M et al. Human retinal epithelium produces and responds to placenta growth factor. Graefes Arch Clin Exp Ophthalmol 2006; 244: 732-741
• 29 Miyamoto N, de Kozak Y, Normand N et al. PlGF-1 and VEGFR-1 pathway regulation of the external epithelial hemato-ocular barrier. A model for retinal edema. Ophthalmic Res 2008; 40: 203-207
• 30 Cai J, Wu L, Qi X, Shaw L et al. Placenta growth factor-1 exerts time-dependent stabilization of adherens junctions following VEGF-induced vascular permeability. PLoS One 2011; 6: e18076
• 31 Deissler HL, Deissler H, Lang GK et al. VEGF but not PlGF disturbs the barrier of retinal endothelial cells. Exp Eye Res 2013; 115: 162-171
• 32 Clauss M, Weich H, Breier G et al. 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: 17629-17634
• 33 Perelman N, Selvaraj SK, Batra S et al. Placenta growth factor activates monocytes and correlates with sickle cell disease severity. Blood 2003; 102: 1506-1514
• 34 Bottomley MJ, Webb NJ, Watson CJ et al. Placenta growth factor (PlGF) induces vascular endothelial growth factor (VEGF) secretion from mononuclear cells and is co-expressed with VEGF in synovial fluid. Clin Exp Immunol 2000; 119: 182-188
• 35 Kim KJ, Cho CS, Kim WU. Role of placenta growth factor in cancer and inflammation. Exp Mol Med 2012; 44: 10-19
• 36 Shibuya M. Vascular endothelial growth factor-dependent and -independent regulation of angiogenesis. BMB Rep 2008; 41: 278-286
• 37 Jain RK, Xu L. alphaPlGF: a new kid on the antiangiogenesis block. Cell 2007; 131: 443-445
• 38 Simpson DA, Murphy GM, Bhaduri T et al. Expression of the VEGF gene family during retinal vaso-obliteration and hypoxia. Biochem Biophys Res Commun 1999; 262: 333-340
• 39 Shen J, Xie B, Dong A et al. In vivo immunostaining demonstrates macrophages associate with growing and regressing vessels. Invest Ophthalmol Vis Sci 2007; 48: 4335-4341
• 40 Kowalczuk L, Touchard E, Omri S et al. Placental growth factor contributes to micro-vascular abnormalization and blood-retinal barrier breakdown in diabetic retinopathy. PLoS One 2011; 6: e17462
• 41 Huang H, He J, Johnson D et al. Deletion of placental growth factor prevents diabetic retinopathy and is associated with Akt activation and HIF1α-VEGF pathway inhibition. Diabetes 2015; 64: 200-212
• 42 Nourinia R, Soheili ZS, Ahmadieh H et al. Knockdown of the placental growth factor gene inhibits laser induced choroidal neovascularization in a murine model. J Ophthalmic Vis Res 2013; 8: 4-8
• 43 Otani A, Takagi H, Oh H et al. Vascular endothelial growth factor family and receptor expression in human choroidal neovascular membranes. Microvasc Res 2002; 64: 162-169
• 44 Muether PS, Neuhann I, Buhl C et al. Intraocular growth factors and cytokines in patients with dry and neovascular age-related macular degeneration. Retina 2013; 33: 1809-1814
• 45 Mitamura Y, Tashimo A, Nakamura Y et al. Vitreous levels of placenta growth factor and vascular endothelial growth factor in patients with proliferative diabetic retinopathy. Diabetes Care 2002; 25: 2352
• 46 Yamashita H, Eguchi S, Watanabe K et al. Expression of placenta growth factor (PIGF) in ischaemic retinal diseases. Eye (Lond) 1999; 13: 372-374
• 47 Ando R, Noda K, Namba S et al. Aqueous humour levels of placental growth factor in diabetic retinopathy. Acta Ophthalmol 2014; 92: e245-246
• 48 Chen X, Li J, Li M et al. KH902 suppresses high glucose-induced migration and sprouting of human retinal endothelial cells by blocking VEGF and PIGF. Diabetes Obes Metab 2013; 15: 224-233
• 49 Boyd SR, Zachary I, Chakravarthy U et al. Correlation of increased vascular endothelial growth factor with neovascularization and permeability in ischemic central vein occlusion. Arch Ophthalmol 2002; 120: 1644-1650
• 50 Noma H, Mimura T, Shimada K. Role of inflammation in previously untreated macular edema with branch retinal vein occlusion. BMC Ophthalmol 2014; 14: 67
• 51 Martinsson-Niskanen T, Riisbro R, Larsson L et al. Monoclonal antibody TB-403: a first-in-human, Phase I, double-blind, dose escalation study directed against placental growth factor in healthy male subjects. Clin Ther 2011; 33: 1142-1149
• 52 Lassen U, Nielsen DL, Sørensen M et al. A phase I, dose-escalation study of TB-403, a monoclonal antibody directed against PlGF, in patients with advanced solid tumours. Br J Cancer 2012; 106: 678-684
• 53 Van de Veire S, Stalmans I, Heindryckx F et al. Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease. Cell 2010; 141: 178-190
• 54 Zheng Y, Gu Q, Xu X. Inhibition of ocular neovascularization by a novel peptide derived from human placenta growth factor-1. Acta Ophthalmol 2012; 90: e512-523
• 55 Lang GE, Lang GK, Deissler HL. Grundlegende In-vitro-Untersuchungen zur VEGF-Inhibition mit Aflibercept: Gemeinsamkeiten und Unterschiede zu anderen VEGF-bindenden therapeutischen Proteinen. Klin Monatsbl Augenheilkd 2015; 232: 295-302
• 56 Holash J, Davis S, Papadopoulos N et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A 2002; 99: 11393-11398
• 57 Huang J, Li X, Li M et al. Effects of intravitreal injection of KH902, a vascular endothelial growth factor receptor decoy, on the retinas of streptozotocin-induced diabetic rats. Diabetes Obes Metab 2012; 14: 644-653
• 58 Wang Q, Li T, Wu Z et al. Novel VEGF decoy receptor fusion protein conbercept targeting multiple VEGF isoforms provide remarkable anti-angiogenesis effect in vivo. PLoS One 2013; 8: e70544
• 59 Huang H, Shen J, Vinores SA. Blockade of VEGFR1 and 2 suppresses pathological angiogenesis and vascular leakage in the eye. PLoS One 2011; 6: e21411
• 60 Van Bergen T, Jonckx B, Hollanders K et al. Inhibition of placental growth factor improves surgical outcome of glaucoma surgery. J Cell Mol Med 2013; 17: 1632-1643
• 61 Haller JA, Bandello F, Belfort jr. R et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010; 117: 1134-1146
• 62 Boyer DS, Yoon YH, Belfort jr. R et al. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology 2014; 121: 1904-1914
• 63 Martidis A, Duker JS, Greenberg PB et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology 2002; 109: 920-927
• 64 Ip MS, Scott IU, VanVeldhuisen PC et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs. Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol 2009; 127: 1101-1114
• 65 Jonas JB, Kreissig I, Degenring R. Intravitreal triamcinolone acetonide for treatment of intraocular proliferative, exudative, and neovascular diseases. Prog Retin Eye Res 2005; 24: 587-611
• 66 Wilson CA, Berkowitz BA, Sato Y et al. Treatment with intravitreal steroid reduces blood-retinal barrier breakdown due to retinal photocoagulation. Arch Ophthalmol 1992; 110: 1155-1159
• 67 Fischer C, Mazzone M, Jonckx B et al. FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy?. Nat Rev Cancer 2008; 8: 942-956
• 68 Diabetic Retinopathy Clinical Research Network. Wells JA, Glassman AR et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 2015; 372: 1193-1203
• 69 Li X, Xu G, Wang Y et al. Safety and efficacy of conbercept in neovascular age-related macular degeneration: results from a 12-month randomized phase 2 study: AURORA study. Ophthalmology 2014; 121: 1740-1748