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Increase in vascular permeability occurs under many physiological conditionsand is central in diverse human pathologies. Thrombin is a pro-coagulant serineprotease, which causes the local loss of endothelial barrier integrity therebyenabling the rapid extravasation of plasma proteins and the local formation offibrin-containing clots. Available information suggests that thrombin inducesendothelial permeability by promoting actomyosin contractility through theRho/ROCK signaling pathway. Here we took advantage of pharmacologicalinhibitors, knockdown approaches, and the emerging knowledge on howpermeability factors affect endothelial junctions to investigate in detail themechanism underlying thrombin-induced endothelial permeability. We show thatthrombin signals through PAR-1 and its coupled G proteins G(12/13) and G(11/q)to induce RhoA activation and intracellular calcium elevation, and that theseevents are interrelated. In turn, this leads to the stimulation of ROCK, whichcauses actin stress-fiber formation. However, this alone is not sufficient toaccount for thrombin-induced permeability. Instead, we found that proteinkinase C-related kinase, a Rho-dependent S/T kinase, is activated inendothelial cells upon thrombin stimulation and that its expression is requiredfor endothelial permeability and remodeling of cell-extracellular matrix andcell-cell adhesions. Our results demonstrate that the signal initiated bythrombin bifurcates at the level of RhoA to promote changes in the cytoskeletalarchitecture through ROCK and the remodeling of focal adhesion componentsthrough PRK. Ultimately, both pathways converge to cause cell-cell junctiondisruption and provoke vascular leakage.

journal of biological chemistry/the journal of biological chemistry

Protein Kinase C-related Kinase and ROCK Are Required for  Thrombin-induced Endothelial Cell Permeability Downstream from G{alpha}12/13  and G{alpha}11/q