Universität zu Köln

Balser, Carsten, Wolf, Anne ORCID: 0000-0003-2551-9821, Herb, Marc ORCID: 0000-0002-7533-0288 and Langmann, Thomas (2019). Co-inhibition of PGF and VEGF blocks their expression in mononuclear phagocytes and limits neovascularization and leakage in the murine retina. J. Neuroinflamm., 16. LONDON: BMC. ISSN 1742-2094

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Abstract

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 7days 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Balser, Carsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Wolf, Anne UNSPECIFIED orcid.org/0000-0003-2551-9821 UNSPECIFIED Herb, Marc UNSPECIFIED orcid.org/0000-0002-7533-0288 UNSPECIFIED Langmann, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-156869
DOI:	10.1186/s12974-019-1419-2
Journal or Publication Title:	J. Neuroinflamm.
Volume:	16
Date:	2019
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1742-2094
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PLACENTAL GROWTH-FACTOR; MACULAR DEGENERATION; INFLAMMASOME ACTIVATION; AFLIBERCEPT; MICROGLIA; BREAKDOWN; CELLS Multiple languages Immunology; Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15686