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1 Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa, USA; Department of Biomedical Engineering, University of Iowa College of Engineering, Iowa City, Iowa, USA
2 Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa, USA
3 Department of Physiology Program, Harvard School of Public Health, Boston, MA, USA
4 Department of Mechanical, Aerospace and Biomedical Engineering, University of Tennessee, Knoxville, Tennessee, USA
* To whom correspondence should be addressed. E-mail: alan-moy{at}uiowa.edu.
The mechanisms of phorbol ester and thrombin-mediated pulmonary artery endothelial barrier dysfunction were compared. PDBU mediated slow force velocity and less force than thrombin. Taxol did not attenuate PDBU-mediated tension, while it reversed nocodazole-mediated tension. PDBU-mediated tension was not affected by acrylamide; PDBU increased cell stiffness and produced greater declines in transendothelial resistance (TER) than acrylamide. Thus, PDBU caused a net increase in tension, and did not unload microtubule or intermediate filaments. Microfilament remodeling, based on immunocytochemistry and actin solubility, lacked the sensitivity and specificity to predict actin-dependent mechanical properties. Thrombin increased MLCK site-specific MLC phosphorylation based on peptide map analysis, while PDBU did not increase PKC-specific MLC phosphorylation. The initial PDBU-mediated tension development temporally correlated with PDBU-mediated decline in TER and increased l-caldesmon phosphorylation. PDBU-mediated tension development and decreases in TER was associated with a temporal loss of endothelial cell-matrix adhesion based on a numerical model of TER. Although thrombin-mediated tension was associated with actin insolubility, actin reorganization and gap formation based on immunocytochemistry, these changes did not predict thrombin-mediated gap formation based on TER and time-lapsed DIC microscopy. These data suggest that PDBU may disrupt endothelial barrier function through loss of cell-matrix adhesion through l-CaD -dependent actin contraction.
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