Structural Mechanisms in the Abolishment of VEGF-induced Microvascular Hyperpermeability by cAMP

To investigate the structural mechanisms by which elevation of the intraendothelial cAMP levels abolishes or attenuates the transient increase in microvascular permeability by vascular endothelial growth factor (VEGF), we examined cAMP effect on VEGF-induced hyperpermeability to small solute sodium fluorescein (Stokes $radius=0.45nm$⁠) $Psodiumfluorescein$⁠, intermediate-sized solute $α$-lactalbumin (Stokes $radius=2.01nm$⁠) $Pα-lactalbumin$⁠, and large solute albumin (BSA, Stokes $radius=3.5nm$⁠) $PBSA$ on individually perfused microvessels of frog mesenteries. After $20min$ pretreatment of $2mM$ cAMP analog, 8-bromo-cAMP, the initial increase by $1nM$ VEGF was completely abolished in $Psodiumfluorescein$ (from a peak increase of $2.6±0.37$ times control with VEGF alone to $0.96±0.07$ times control with VEGF and cAMP), in $Pα-lactalbumin$ (from a peak increase of $2.7±0.33$ times control with VEGF alone to $0.76±0.07$ times control with VEGF and cAMP), and in $PBSA$ (from a peak increase of $6.5±1.0$ times control with VEGF alone to $0.97±0.08$ times control with VEGF and cAMP). Based on these measured data, the prediction from our mathematical models suggested that the increase in the number of tight junction strands in the cleft between endothelial cells forming the microvessel wall is one of the mechanisms for the abolishment of VEGF-induced hyperpermeability by cAMP.