Pigment Epithelium-Derived Factor Binding to VEGFR-1 (Flt-1) Increases the Survival of Retinal Neurons.

Autor:	Meng J; Department of Ophthalmology and Eye Hospital, Leipzig University, Leipzig, Germany., Yang XM; Department of Ophthalmology, PLA Army General Hospital, Beijing, China., Scheer O; Department of Ophthalmology and Eye Hospital, Leipzig University, Leipzig, Germany., Lange J; Norwegian Centre for Movement Disorders, Stavanger University Hospital, Norway., Müller H; Department of Ophthalmology and Eye Hospital, Leipzig University, Leipzig, Germany., Bürger S; Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Leipzig, Germany., Rothemund S; Core Unit Peptide Technologies, Medical Faculty, Leipzig University, Leipzig, Germany., Younis R; Department of Ophthalmology and Eye Hospital, Leipzig University, Leipzig, Germany., Unterlauft JD; Department of Ophthalmology, University Hospital, Inselspital, Bern, Switzerland., Eichler W; Department of Ophthalmology and Eye Hospital, Leipzig University, Leipzig, Germany.
Jazyk:	angličtina
Zdroj:	Investigative ophthalmology & visual science [Invest Ophthalmol Vis Sci] 2024 Aug 01; Vol. 65 (10), pp. 27.
DOI:	10.1167/iovs.65.10.27
Abstrakt:	Purpose: The purpose of this study was to examine possible involvement of vascular endothelial growth factor (VEGF) receptor (VEGFR)-1/Flt-1 in pigment epithelium-derived factor (PEDF)-promoted survival of retinal neurons. Methods: Survival of growth factor-deprived retinal ganglion cells (RGCs) and R28 cells and activation of ERK-1/-2 MAP kinases were assessed in the presence of PEDF, placental growth factor (PlGF), and VEGF using cell cultures, viability assays and quantitation of ERK-1/-2 phosphorylation. VEGFR-1/Flt-1 expression was determined using quantitative PCR (qPCR) and Western blotting. VEGFR-1/Flt-1 was knocked down in R28 cells by small interfering RNA (siRNA). Binding of a PEDF-IgG Fc fusion protein (PEDF-Fc) to retinal neurons, immobilized VEGFR-1/Flt-1 and VEGFR-1/Flt-1-derived peptides was studied using binding assays and peptide scanning. Results: PEDF in combination with PlGF stimulated increased cell survival and ERK-1/-2 MAP kinase activation compared to effects of either factor alone. VEGFR-1/Flt-1 expression in RGCs and R28 cells was significantly upregulated by hypoxia, VEGF, and PEDF. VEGFR-1/Flt-1 ligands (VEGF and PlGF) or soluble VEGFR-1 (sflt-1) competed with PEDF-Fc for binding to R28 cells. Depleting R28 cells of VEGFR-1/Flt-1 resulted in reduced PEDF-Fc binding when comparing VEGFR-1/Flt-1 siRNA- and control siRNA-treated cells. PEDF-Fc interacted with immobilized sflt-1, which was specifically blocked by VEGF and PlGF. PEDF-Fc binding sites were mapped to VEGFR-1/Flt-1 extracellular domains D3 and D4. Peptides corresponding to D3 and D4 specifically inhibited PEDF-Fc binding to R28 cells. These peptides and sflt-1 significantly inhibited PEDF-promoted survival of R28 cells. Conclusions: These results suggest that PEDF can target VEGFR-1/Flt-1 and this interaction plays a significant role in PEDF-mediated neuroprotection in the retina.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu