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Cyclic Adenosine Monophosphate Protects Endothelial Barrier Function Independent of Inhibiting 20-kd Myosin Light Chain-Dependent Tension Development^*

^* From the Department of Internal Medicine and the Department of Biomedical Engineering, University of Iowa College of Medicine, Iowa City, IA.

Correspondence to: Alan Moy, MD, University of Iowa College of Medicine, 200 Hawkins Dr., Iowa City, IA 52242-1081

We sought to directly test the hypothesis that cyclic adenosine monophosphate (cAMP) protects endothelial barrier function through inhibition of 20-kd myosin light chain (MLC₂₀)-dependent tension development. We previously reported that thrombin and histamine initiate a disruption in transendothelial resistance, a dynamic and quantitative index of endothelial barrier function, across cultured human umbilical vein endothelial cells independent of tension development. However, the restoration of barrier function in response to thrombin was dependent on MLC₂₀-dependent and independent pathways. Thus, cAMP could protect barrier function by accelerating restoration of barrier function through a MLC₂₀-sensitive pathway. Alternatively, cAMP might act by preventing a MLC₂₀-insensitive disruption of barrier function or by accelerating restoration of barrier function through a MLC₂₀-insensitive pathway.

Exposure of cultured human umbilical vein endothelial cells HUVEC to the cAMP agonists, theophylline and forskolin, decreased constitutive isometric tension of a confluent monolayer inoculated on a collagen membrane, but it did not prevent increased tension in thrombin-treated cells. The inability of cAMP agonists to prevent tension development correlated with an inability of cAMP stimulation to prevent increased MLC₂₀ phosphorylation in response to thrombin. While cAMP did not prevent tension development or increased MLC₂₀ phosphorylation, cAMP attenuated the effect of thrombin on transendothelial resistance, an index of barrier function, across a confluent monolayer inoculated on a gold microelectrode. Activation of cAMP-dependent signal transduction more promptly restored transendothelial resistance to initial basal levels (10 min) compared with thrombin only (60 min). However, cAMP stimulation did not prevent the decline in resistance in thrombin-treated cells. ML-7, a myosin light chain kinase antagonist that attenuated increased MLC₂₀ phosphorylation and tension development, also restored transendothelial resistance more rapidly than thrombin alone (20 min), but at a slower rate than cAMP.

These data demonstrate that activation of cAMP-dependent signal transduction protects barrier function independent of inhibition of MLC₂₀-dependent tension development. Instead, activation of cAMP-dependent signal transduction pathways protects barrier function, in part, by uncoupling the load of increased MLC₂₀-dependent tension development.

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This Article Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Moy, A. B. Articles by Shasby, D. M. Search for Related Content PubMed PubMed Citation Articles by Moy, A. B. Articles by Shasby, D. M.