Combinatory inhibition of VEGF and FGF2 is superior to solitary VEGF inhibition in an in vitro model of RPE-induced angiogenesis

Stahl, Andreas; Paschek, L.; Martin, Gottfried; Feltgen, Nicolas; Hansen, Lutz L.; Agostini, Hansjürgen

doi:10.1007/s00417-009-1058-x

Cited by 41 publications

(29 citation statements)

References 32 publications

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“…Studies about the role of FGF-2 in the de-velopment of CNV showed that FGF-2 can indirectly induce the neovascularisation formation via upregulation of VEGF and increasing the proliferation of endothelial cells [43][44][45] . Stahl et al [26] reported that combined inhibition of VEGF and FGF-2 was a superior therapy compared to single inhibition of VEGF in the treatment of CNV. Hu et al [27] found that the mRNA and protein level of FGF-2 in the RPE and RPE/choroidal tissues increased quickly within hours after a laser treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Apart from VEGF, other pro-angiogenic factors like PDGF-β [17,24,25] , FGF [26][27][28][29] , TGF-β [17,[29][30][31][32] , and IL-8 [33][34][35][36] were also reported to be involved in the pathological process of AMD. Zehetner et al [24] compared the plasma levels of PDGF-β in neovascular AMD patients with healthy controls and found that there was a significantly higher plasma PDGF-β level in neovascular AMD patients than in healthy controls.…”

Section: Discussionmentioning

confidence: 99%

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Behaviour of CD11b-Positive Cells in an Animal Model of Laser-Induced Choroidal Neovascularisation

Heiduschka

Alex

et al. 2017

Ophthalmologica

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Background/Aim: Immune cells, e.g. microglial cells of the retina, appear to be involved in pathological processes in neovascular age-related macular degeneration. Therefore, the purpose of this study was to immunohistochemically check the expression of various factors and cytokines by CD11b-positive (CD11b+) immune cells in an animal model of choroidal neovascularisation (CNV). Methods: We used the animal model of laser-induced CNV in mice. Eyes were isolated at 1, 4, 7, and 14 days after laser treatment. Cryosections were prepared and checked immunohistochemically for the presence of different growth factors and cytokines on microglial cells and other immune cells identified by CD11b immunoreactivity. Results: We found that the number of CD11b+ cells at the laser spots increased dramatically 4 days after laser treatment, the majority of them entering the laser spot most probably by migration. CD11b+ cells in the laser spot were positive for a variety of pro-angiogenic factors, such as PDGF-β, FGF-1, FGF-2, and TGF-β₁. They were also positive for some inflammatory cytokines, in particular TNF-α, IL-6, and CXCL1. In non-treated retinas, CD11b+ cells showed almost no immunoreactivity for these proteins. Conclusion: Microglial cells, macrophages, and other CD11b+ cells may promote the neovascularisation in the laser spot and show a moderate inflammatory behaviour. Immunoreactivity for most of these molecules was found to decrease during the time of observation. Modulation of immune cell activity may thus be a tool to reduce the extent of CNV.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Behaviour of CD11b-Positive Cells in an Animal Model of Laser-Induced Choroidal Neovascularisation

Heiduschka

Alex

et al. 2017

Ophthalmologica

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“…PDGF-DD inhibition thus attenuated the availability of multiple cellular components needed for pathological angiogenesis. In addition, PDGF-DD is a potent regulator of the expression of numerous proangiogenic and proapoptotic genes involved in pathological angiogenesis, such as VEGF, FGF2, PlGF, and VEGF-B, important players in CNV (25,(31)(32)(33)(34), Dcn and TNF-␣, apoptosis inducers and inhibitors of PDGF-induced vascular cell proliferation, migration, and survival (36 -39). Apoptosis occurs in the neovasculature during pathological angiogenesis (77,78).…”

Section: Discussionmentioning

confidence: 99%

“…3, A and B, n ϭ 8). These genes included fibroblast growth factor 2 (FGF2), vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and VEGF-B, which play important roles in CNV (25,(31)(32)(33)(34). At day 3 after CNV, which is an early stage of CNV (35), the downregulation of the proangiogenic genes was moderate (Fig.…”

Section: Pdgf-dd Regulates the Expression Of Many Proangiogenic And Pmentioning

confidence: 99%

Platelet-derived Growth Factor-DD Targeting Arrests Pathological Angiogenesis by Modulating Glycogen Synthase Kinase-3β Phosphorylation

Kumar

Lee

et al. 2010

Journal of Biological Chemistry

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Platelet-derived growth factor-DD (PDGF-DD) is a recently discovered member of the PDGF family. The role of PDGF-DD in pathological angiogenesis and the underlying cellular and molecular mechanisms remain largely unexplored. In this study, using different animal models, we showed that PDGF-DD expression was up-regulated during pathological angiogenesis, and inhibition of PDGF-DD suppressed both choroidal and retinal neovascularization. We also demonstrated a novel mechanism mediating the function of PDGF-DD. PDGF-DD induced glycogen synthase kinase-3␤ (GSK3␤) Ser 9 phosphorylation and Tyr 216 dephosphorylation in vitro and in vivo, leading to increased cell survival. Consistently, GSK3␤ activity was required for the antiangiogenic effect of PDGF-DD targeting. Moreover, PDGF-DD regulated the expression of GSK3␤ and many other genes important for angiogenesis and apoptosis. Thus, we identified PDGF-DD as an important target gene for antiangiogenic therapy due to its pleiotropic effects on vascular and non-vascular cells. PDGF-DD inhibition may offer new therapeutic options to treat neovascular diseases.

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“…In contrast, FGF2 was more prevalent in CNV-RPE-69. FGF2 has been identified as a target for intravitreal therapy, especially in combination with anti-VEGF [27,28]. Neuropilin 1 has been associated with CNV formation [29][30][31], but was only upregulated in 1 CNV membrane.…”

Section: Discussionmentioning

confidence: 99%

Expression of Angiogenic and Inflammatory Factors in Choroidal Neovascularisation-Derived Retinal Pigment Epithelium

Ehlken

Guichard²,

Schlunck³

et al. 2017

Ophthalmic Res

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Purpose: Anti-angiogenic treatment is well established in the management of exudative age-related macular degeneration (AMD), but not sufficient in all patients. The characterisation of factors driving this chronic disease could serve to identify additional treatment options. The purpose of this study was to assess gene expression patterns and distinct changes in cells derived from surgically extracted choroidal neovascularisation (CNV) membranes. Materials and Methods: The expression of >11,000 genes was analysed by means of a microarray in cells cultured from 2 late-stage CNV membranes compared to primary human retinal pigment epithelium (RPE) and ARPE-19 cells. A pathway analysis was performed to identify gene expression patterns associated with exudative AMD. Results: The analysis revealed significant alterations in gene sets associated with inflammatory processes in CNV-derived cells, involving the upregulation of pro-inflammatory factors IL6, C3, and C5, and downregulation of anti-inflammatory complement factor B and complement factor I. Factors associated with angiogenesis, such as VEGFA or ANGPT2, were not significantly regulated in the 2 RPE-derived cell lines. Conclusion: In late-stage CNV membrane-derived RPE, gene expression was shifted towards a pro-inflammatory state. Angiogenesis-associated factors were regulated differently in the 2 CNV-derived RPE membranes. While inflammation seems to be continuously stimulated by RPE associated with late exudative AMD, this appears not to be the case with regard to angioregulatory mechanisms.

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Combinatory inhibition of VEGF and FGF2 is superior to solitary VEGF inhibition in an in vitro model of RPE-induced angiogenesis

Abstract: RPE from CNV patients expresses angiogenic growth factors that act in part independently of VEGF. Targeted combinatory therapy can be superior to solitary anti-VEGF therapy. One possible candidate for combinatory therapy is FGF2.

Cited by 41 publications

References 32 publications

Behaviour of CD11b-Positive Cells in an Animal Model of Laser-Induced Choroidal Neovascularisation

Behaviour of CD11b-Positive Cells in an Animal Model of Laser-Induced Choroidal Neovascularisation

Platelet-derived Growth Factor-DD Targeting Arrests Pathological Angiogenesis by Modulating Glycogen Synthase Kinase-3β Phosphorylation

Expression of Angiogenic and Inflammatory Factors in Choroidal Neovascularisation-Derived Retinal Pigment Epithelium

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