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Effect of VEGF on Retinal Microvascular Endothelial Hydraulic Conductivity: The Role of NO

¹ From The Pennsylvania State University, Biomolecular Transport Dynamics Laboratory, Department of Chemical Engineering, University Park; and ² The Penn State Retina Research Group, Departments of Cellular and Molecular Physiology and Ophthalmology, Penn State University College of Medicine, Hershey, Pennsylvania.

PURPOSE. Vascular endothelial growth factor (VEGF) increases microvascular permeability in vivo and has been hypothesized to play a role in plasma leakage in diabetic retinopathy. Few controlled studies have been conducted to determine the mechanism underlying the effect of VEGF on transport properties (e.g., hydraulic conductivity [Lp]). This study was conducted to determine the effect of VEGF on bovine retinal microvascular endothelial Lp and the role of nitric oxide (NO) and the guanylate cyclase/guanosine 3',5'-cyclic monophosphate/protein kinase G (GC/cGMP/PKG) pathway downstream of NO in mediating the VEGF response.

METHODS. Bovine retinal microvascular endothelial cells (BRECs) were grown on porous polycarbonate filters, and water flux across BREC monolayers in response to a pressure differential was measured to determine endothelial Lp.

RESULTS. VEGF (100 ng/ml) increased endothelial Lp within 30 minutes of addition and by 13.8-fold at the end of 3 hours of exposure. VEGF stimulated endothelial monolayers to release NO and incubation of the BRECs with the nitric oxide synthase inhibitor N^G-monomethyl-L-arginine (L-NMMA; 100 µM) significantly attenuated the VEGF-induced Lp increase. It was observed that incubation of the monolayers with the GC inhibitor LY-83583 (10 µM) did not alter the VEGF-mediated Lp response. Addition of the cGMP analogue 8-br-cGMP (1 mM) did not change the baseline Lp over 4 hours. Also, the PKG inhibitor KT5823 (1 µM) did not inhibit the response of BREC Lp to VEGF.

CONCLUSIONS. These experiments indicate that VEGF elevates hydraulic conductivity in BRECs through a signaling mechanism that involves NO but not the GC/cGMP/PKG pathway.

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