Purpose : It has been suggested that PlGF, as a key member of the VEGF-family, is associated with pathological angiogenesis, vasopermeability and neuroglial dysfunction in the inner retina (see review in Prog Ret Eye Res DOI: 10.1016/j.preteyeres.2018.10.006). Recent studies have indicated that PlGF may also play a role in outer retinal disease. We hypothesise that activation of the PlGF receptor pathway plays a pathogenic role in RPE dysfunction. Methods : Localisation of PlGF and its cognate receptors VEGFR-1 and neuropilin-1 (NRP-1) was assessed in murine and human retinal tissues using immunohistochemistry. Signalling responses to human recombinant PlGF was investigated in ARPE-19 and human foetal RPE (hfRPE). Tight junction integrity and RPE barrier properties were evaluated in ARPE-19 and hfRPE using transepithelial electrical resistance (TEER) measured at baseline and 24 hours after PlGF exposure in both normoxic and hypoxic conditions. A parallel assessment was made of RPE viability following PlGF exposure. Results : PlGF, VEGFR-1 and NRP-1 were localised to vascular cells, Müller glia and RPE in the retina. In vitro, the RPE demonstrated activation of VEGFR-1 and ERK1/2 upon exposure to PlGF (50ng/mL). PlGF disrupted integrity of the RPE tight junctions which was observed through mis-localisation of ZO-1. In terms of TEER, 50ng/mL PlGF reduced ARPE-19 ohms.cm2 by 32% (±2.63%) and hfRPE ohms.cm2 by 63% (±8.3%) and this was significantly different between control and 50ng/mL groups (ARPE-19 p <0.005; hfRPE p<0.05). There was no significant change in cell numbers however PlGF was associated with reduced RPE viability. Hypoxia exacerbated these PlGF effects in RPE. Conclusions : The key elements of the PlGF signalling pathway are present in human RPE in vitro and in vivo. PlGF has been shown to be upregulated in many disease scenarios and exposure to this growth factor compromises the RPE barrier suggesting that manipulation of this pathway could offer therapeutic benefits. This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
|Publication status||Published - Jul 2019|
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Regulating the bioactivity of placental growth factor in the aging outer retina as a new therapeutic approach to age-related macular degenerationAuthor: Cunningham, F., Jul 2021
Student thesis: Doctoral Thesis › Doctor of Philosophy