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M. Abdulrazik, N. Miyamoto, F. Behar-Cohen; Placental Growth Factor-1 for Reversible Enhancement of Blood-Retinal Barrier Permeability: A Royal Gate for Targeting the Retina. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5009.
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Several hydrophilic macromolecules have been suggested recently as potential retinal therapeutics. However, their permeation through blood-retinal barriers toward the retina is poor due to high molecular weight and hydrophilicity. We aimed to study the effect of placental growth factor-1 (PlGF-1) on the permeability of blood-retinal barriers to hydrophilic macromolecules.
Cultured ARPE-19 cells were treated with PlGF-1 and changes in transepithelial electrical resistance (TER) were monitored. Immuno-localization of retinal pigment epithelium (RPE) tight-junction associated protein ZO-1 was done on RPE-choroid flat mounts from rat eyes after intravitreal PlGF-1 or PBS injection. The effect of PlGF-1 intervention was observed by confocal microscopy. Rats received intravitreal injection of PlGF-1 or PBS. After 24 hours, animals received either subconjunctival or intravenous tail vein injection of 40kDa dextran solution. Rats were sacrificed at different time points after dextran injection and enucleated eyes were snap-frozen and processed for visualization by fluorescence microscopy.
The pattern of change in TER from baseline values by time following PlGF-1 intervention have shown sharp decline in first hour with a plateau reached at six hours and maintained up to 24 hours around 40% of baseline values. In control eyes, RPE cells displayed regular tight junctions. Six hours after PlGF-1 intervention, spaces between cells showed unsealed junctions with occludin migrating from cell membrane to the cytoplasm and nucleus. Four days after PlGF-1 intervention, the initial regular distribution of occluding in the tight junction was reformed. In PlGF-1 treated eyes, contrary to control group eyes, the subconjunctival 40kDa dextran penetrated the RPE barrier and accumulated in the retina. A patchy penetration pattern was observed being prominent next to choroidal collecting venules. Following intravenous administration the 40kDa dextran penetrated the endothelial barrier of retinal vessels and accumulated in the retina, but only in PlGF-1 treated eyes.
PlGF-1 intervention has caused a reversible enhancement of RPE permeability and allowed the permeation of 40kDa dextran through RPE and endothelial barriers towards the retina. The results suggest a novel avenue for efficient delivery of hydrophilic macromolecules to the retina.
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