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Maria Llorian-Salvador, Judith Lechner, Peter Barabas, Eimear Byrne, Josy Augustine, Tim M Curtis, Mei Chen, Heping Xu; VEGF-B protects Müller cells from hypoxic- and oxidative stress-mediated damage. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1675.
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© ARVO (1962-2015); The Authors (2016-present)
Müller cells play an important role in retinal pathophysiology. Müller cell-derived vascular endothelial growth factor (VEGF) is critically involved in retinal cell survival and function, although pathological levels of VEGF can lead to retinal vascular and angiogenic diseases. There are different isoforms of VEGF and the role of VEGF-A in retinal health and disease has been studied extensively. The role of other VEGF isoforms in retinal pathophysiology, however, remains poorly-defined. This study investigated the role of VEGF-B in Muller cells under hypoxic and oxidative conditions.
The expression profiles of VEGF and VEGFRs in primary murine Müller cells and the mouse Müller cell line QMMuC1 were examined by RT-PCR, ELISA and Western Blot. The effect of VEGF-B neutralizing antibody and recombinant protein on Müller cell viability/survival under normal, hypoxic and oxidative (4-HNE) conditions was evaluated by Alamar Blue, Yo-Pro uptake and immunocytochemistry. Expression of key proteins involved in Muller cell function such as GFAP, AQP4, Kir4.1, GLAST, GS and TRPV4 were examined by RT-PCR, immunocytochemistry and western blot. TRPV4 channel activity was assessed using a Fura-2-based calcium assay.
Among different VEGF members, VEGF-B was expressed at the highest levels in Müller cells. They also expressed high levels of VEGFR1 and the co-receptor NRP1 under normal culture conditions. VEGF-B neutralizing did not affect the viability induce gliosis or modified the expression of proteins involved in functionality Müller cells. 1% O2 and 4-HNE significantly altered the expression of VEGF-B and its receptors in QMMuC1 cells. Blocking VEGF-B and/or VEGFR1 and NRP1 enhanced hypoxia or 4-HNE-induced Müller cell death, accompanied by decreased Kir4.1 and AQP4 expression. We further found that TRPV4 signalling pathway is critically involved in 4-HNE-induced Müller damage and recombinant VEGF-B can block the TRPV4 signalling pathway and reduce Müller cell damage. Under hypoxic conditions, blocking VEGF-B reduces GLAST expression, whereas the addition of recombinant VEGF-B restored GS expression in Müller cells.
VEGF-B critically controls Müller cell functions and acts as a neurotrophic growth factor for these cells.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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