Inhibition of Placenta Growth Factor Reduces Subretinal Mononuclear Phagocyte Accumulation in Choroidal Neovascularization

Crespo-Garcia, Sergio; Corkhill, Caitlin; Davids, Anja‐Maria; Kociok, Norbert; Strauß, Olaf; Joussen, Antonia M.; Reichhart, Nadine

doi:10.1167/iovs.16-21283

Cited by 21 publications

(28 citation statements)

References 48 publications

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“…These results are in accordance with a recent report comparing antibody-mediated PGF inhibition with aflibercept at a later time point (14 days) after laser treatment [17]. In that paper, Crespo-Garcia et al identified higher PGF and VEGF levels in the laser-damaged retina using immunostainings [17]. Here, we significantly expand these findings by showing in situ co-expression of PGF and VEGF by Iba1-positive mononuclear phagocytes in the RPE/choroid complex.…”

Section: Discussionsupporting

confidence: 93%

“…Our data show that the PGF inhibition, especially with aflibercept, dampens vascular leakage and CNV 7 days after laser application. These results are in accordance with a recent report comparing antibody-mediated PGF inhibition with aflibercept at a later time point (14 days) after laser treatment [17]. In that paper, Crespo-Garcia et al identified higher PGF and VEGF levels in the laser-damaged retina using immunostainings [17].…”

Section: Discussionsupporting

confidence: 90%

“…Previous reports have indicated a higher efficacy of co-inhibition of VEGF and PGF in decreasing both retinal leakage and neovascularization compared to VEGF inhibition alone [16, 17]. Our analysis of mononuclear phagocytes in both retinal and RPE/choroidal flat mounts revealed reduced microgliosis in the retina, less mononuclear phagocytes in the RPE/choroid, and significantly lower expression of PGF and VEGF after trapping PGF and VEGF.…”

Section: Discussionsupporting

confidence: 46%

“…Thus, increased PGF has been identified in ocular fluids and tissue from patients with diabetic retinopathy [11, 12]), glaucoma [13], and neovascular AMD [14, 15]. High PGF levels are also present in the murine laser model of choroidal neovascularization, and PGF inhibition by either antibodies [16, 17] or trap molecules [18, 19] limits CNV.…”

Section: Introductionmentioning

confidence: 99%

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Co-inhibition of PGF and VEGF blocks their expression in mononuclear phagocytes and limits neovascularization and leakage in the murine retina

Balser

Wolf

Herb

et al. 2019

J Neuroinflammation

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BackgroundAge-related macular degeneration (AMD) is a leading cause of visual impairment in the elderly. The neovascular (wet) form of AMD can be treated with intravitreal injections of different anti-vascular endothelial growth factor (VEGF) agents. Placental growth factor (PGF) is another member of the VEGF family of cytokines with pro-angiogenic and pro-inflammatory effects. Here, we aimed to compare single and combined inhibition of VEGF-A and PGF in the laser-induced mouse model of choroidal neovascularization (CNV) with a focus on the effects on retinal mononuclear phagocytes.MethodsCNV was induced in C57BL/6J mice using a YAG-Laser. Immediately after laser damage antibodies against VEGF-A (aVEGF), anti-PGF (aPGF), aVEGF combined with aPGF, aflibercept, or IgG control were injected intravitreally in both eyes. Three and 7 days after laser damage, the vascular leakage was determined by fluorescence angiography. Lectin staining of retinal and RPE/choroidal flat mounts was used to monitor CNV. In situ mRNA co-expression of Iba1, VEGF and PGF were quantified using in situ hybridization. Retinal and RPE/choroidal protein levels of VEGF and PGF as well as the pro-inflammatory cytokines IL-6, IL1-beta, and TNF were determined by ELISA.ResultsEarly (day 3) and intermediate (day 7) vascular leakage and CNV were significantly inhibited by PGF and VEGF-A co-inhibition, most effectively with the trap molecule aflibercept. While VEGF-A blockage alone had no effects, trapping PGF especially with aflibercept prevented the accumulation of reactive microglia and macrophages in laser lesions. The lesion-related mRNA expression and secretion of VEGF-A and PGF by mononuclear phagocytes were potently suppressed by PGF and partially by VEGF-A inhibition. Protein levels of IL-6 and IL1-beta were strongly reduced in all treatment groups.ConclusionsRetinal inhibition of PGF in combination with VEGF-A prevents vascular leakage and CNV possibly via modulating their own expression in mononuclear phagocytes. PGF-related, optimized strategies to target inflammation-mediated angiogenesis may help to increase efficacy and reduce non-responders in the treatment of wet AMD patients.Electronic supplementary materialThe online version of this article (10.1186/s12974-019-1419-2) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 46%

Section: Introductionmentioning

confidence: 99%

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Co-inhibition of PGF and VEGF blocks their expression in mononuclear phagocytes and limits neovascularization and leakage in the murine retina

Balser

Wolf

Herb

et al. 2019

J Neuroinflammation

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“…Dennoch ist den Autoren hier ein Einblick in die entzündlichen Vorgänge in der Netzhaut von AMD-Patienten gelungen. Die Daten zur Absenkung des VEGF-A nach Anti-VEGF-A-Behandlung sowie die erhöhten Spiegel an MCP1 bei AMD-Patienten decken sich gut mit den Daten anderer Publikationen [2,3], was belegt, dass die von Motohashi erhobenen Daten aussagekräftig sind. Die Absenkung der inflammatorischen Faktoren nach Aflibercept könnte mit tierexperimentellen Daten korrelieren, in denen gezeigt wurde, das eine Aflibercept-Anwendung bei der Laser-induzierten chorioidalen Neovaskularisation (CNV) die Aktivierung von mononukleären Makrophagen wie Mikroglia hemmen kann.…”

Section: Transfer In Die Praxis Von Prof Dr Olaf Strauß (Berlin)unclassified

Welche Rolle spielen Entzündungsfaktoren bei der altersabhängigen Makuladegeneration?

Strauß¹

2018

Kompass Ophthalmol

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Purpose: To evaluate the dynamic changes of the aqueous humor levels of inflammatory factors between patients receiving intravitreal ranibizumab injection (IRI) and aflibercept injection (IAI) in patients with exudative age-related macular degenera- tion (AMD). Methods: The study was performed on 30 eyes with AMD that were scheduled to receive 3 doses of IRI (15 eyes) or IAI (15 eyes) at monthly intervals. Aqueous humor samples were collected when injection was done. The concentrations of VEGF, mono- cyte chemoattractant protein 1 (MCP-1), platelet-derived growth factor (PDGF)-AA, interleukin (IL)-6, and IL-8 were measured in aqueous humor samples from the 30 AMD patients and 10 cataract patients (as controls) by the suspension array method. Results: Aqueous levels of the inflammatory factors (MCP-1, PDGF-AA, IL-6, and IL-8) were significantly correlated with each other. In both the IRI-treated eyes and the IAI-treated eyes, visual acuity and central macular thickness improved significantly, and the aqueous level of VEGF showed a significant decrease. In IAI-treated eyes, the aqueous levels of MCP-1 and PDGF-AA were significantly decreased at 2 months. Conclusions: These findings suggest that the inflammatory factors are involved in the pathogenesis of AMD and also the possibility that the interaction between these inflammatory factors and IRI or IAI is different.

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Brivanib, a multitargeted small‐molecule tyrosine kinase inhibitor, suppresses laser‐induced CNV in a mouse model of neovascular AMD

Zhu

et al. 2019

Journal Cellular Physiology

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In age-related macular degeneration (AMD), choroidal neovascularization (CNV), a major pathologic feature of neovascular AMD (nAMD), affects 10% of patients, potentially causing serious complications, including vision loss. Vascular endothelial growth factor receptor 2 (VEGFR2) and fibroblast growth factor receptor 1 (FGFR1) contribute to the pathogenesis of CNV. Brivanib is an oral selective dual receptor tyrosine kinase (RTK) inhibitor of FGFRs and VEGFRs, especially VEGFR2 and FGFR1.In this study, brivanib inhibited zebrafish embryonic angiogenesis without impairing neurodevelopment. In a mouse CNV model, brivanib intravitreal injection blocked phosphorylation of FGFR1 and VEGFR2 and reduced CNV leakage, area, and formation without causing intraocular toxicity. Moreover, brivanib oral gavage reduced CNV leakage and area. Accordingly, brivanib remained at high concentrations (above 14,000 ng/ml) in retinal/choroidal/scleral tissues following intravitreal injection. Similarly, brivanib remained at high concentrations (over 10,000 ng/ml) in retinal/choroidal/scleral tissues following oral gavage. Finally, in vitro cell experiments demonstrated that brivanib inhibited the proliferation, migration and tube formation of microvascular endothelial cells. In conclusion, our study suggested that brivanib treatment could be a novel therapeutic strategy for nAMD. K E Y W O R D Sage-related macular degeneration, choroidal neovascularization, fibroblast growth factor receptor 1, receptor tyrosine kinase inhibitor, vascular endothelial growth factor receptor 2 *Lele Li, Manhui Zhu, Aimin Sang, and Dongmei Ding contributed equally to this work.

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Inhibition of Placenta Growth Factor Reduces Subretinal Mononuclear Phagocyte Accumulation in Choroidal Neovascularization

Abstract: The results hint at an interplay between PlGF/VEGFR1 and MPs that is important in the early phase of CNV. A combined inhibition of VEGF-A and PlGF is superior to a specific anti-PlGF treatment in terms of subretinal MP recruitment.

Cited by 21 publications

References 48 publications

Co-inhibition of PGF and VEGF blocks their expression in mononuclear phagocytes and limits neovascularization and leakage in the murine retina

Co-inhibition of PGF and VEGF blocks their expression in mononuclear phagocytes and limits neovascularization and leakage in the murine retina

Welche Rolle spielen Entzündungsfaktoren bei der altersabhängigen Makuladegeneration?

Brivanib, a multitargeted small‐molecule tyrosine kinase inhibitor, suppresses laser‐induced CNV in a mouse model of neovascular AMD

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