Occludin redistribution induced by platelet activating factor in rat mesentery microvessels is blocked by increased cAMP

Abstract

Increased intracellular cAMP blocks the acute hyperpermeability response to inflammatory mediators such as platelet activating factor (PAF) or bradykinin in many models of microvascular permeability. Increased cAMP stabilizes the distribution of several endothelial adhesion molecules (e.g., occludin and VE‐cadherin) against inflammatory mediators in cell culture, but cAMP effects on adhesion molecule distribution has not been extensively investigated in intact microvessels. We tested the hypothesis that pretreatment (30 min) with rolipram (10μM) and forskolin (5μM) (R/F) to elevate intracellular cAMP would block redistribution of occludin that is induced by PAF in single perfused vessels of rat mesentery. In control vessels occludin revealed by immunofluorescence was distributed peripherally, was generally very thin and nearly continuous and co‐localized with VE‐cadherin (VE). Perfusion with PAF (10 nM) induced large acute Lp increases within 5–10 min. In vessels fixed near the peak of PAF Lp response occludin was discontinuous and closely co‐localized with VE. Pretreatment with R/F blocked Lp increases and blocked the discontinuities in the occludin. The results are consistent with the model that increased cAMP acts to stabilize peripheral endothelial adhesion structures, including the tight junction, and the stabilization contributes to blocking acute increases in permeability. NIH 28607.