Vascular endothelial growth factor modulates the function of the retinal pigment epithelium in vivo

Retinal edema, the accumulation of extracellular fluid in the retina is usually attributed to inner blood retina barrier (BRB) leakage. Vascular endothelial growth factor plays an important role in this process. The effects of VEGF on the outer BRB, the RPE, however, have received limited attention. Here, we present a methodology to assess how VEGF modulates the integrity of the RPE barrier in vivo.

Control subretinal blebs (1-5 μL) and blebs containing VEGF (1-100 μg/mL), placental growth factor (PlGF; 100 μg/mL), or albumin (100-1000 μg/mL) were injected into New Zealand White or Dutch Belted rabbits with IOP maintained at 10, 15, or 20 mm Hg. One-hour intravitreal pretreatment with ZM323881 (10 μM/L) was used to inhibit the VEGF response. Fluid resorption was followed by optical coherence tomography for 1 hour. Retinal pigment epithelium leakage was assessed by fluorescein angiography.

Increasing IOP resulted in an elevated rate of bleb resorption, while increasing albumin concentration in the bleb decreased the rate of resorption. Vascular endothelial growth factor, but not PlGF, caused a significant, concentration-dependent decrease in the rate of fluid resorption, which was reversed by ZM323881. Compared with albumin-filled blebs, VEGF-filled blebs showed accelerated early-phase leakage from the choroid.

Consistent with a localized modulation of RPE function, VEGF induced a significant reduction in fluid resorption and an increase in hydraulic conductivity. Our results establish VEGF as a major cytokine regulating RPE barrier properties in vivo and indicate that the RPE is a principal factor in the pathogenesis of retinal edema.