FIGURE 6.

Signaling model and molecular mechanisms involved in thrombin-induced permeability. Thrombin induces the activation of its cognate receptor, PAR-1, which is coupled to Gα_11/q and Gα_12/13 signaling. Knockdown experiments showed that Gα_11/q is required for both calcium entry and RhoA activation upon thrombin exposure, whereas Gα_12/13 cooperates in RhoA activation. This dual coupling might regulate the activity and localization and cycling of multiple RhoGEFs. RhoA is then central in the thrombin-induced increase of permeability in endothelial cells, as it triggers the activation of two essential downstream effectors, ROCK and PRK. In addition, RhoA can control formin activity on actin and microtubule organization. ROCK activity is required for actomyosin contractility through the regulation of MLC and cofilin and the actin stress fiber architecture. Conversely, PRK expression contributes to FAK and paxillin phosphorylations and the proper focal adhesion morphology. Finally, both signaling routes converge on the increase of actomyosin contractility and cell-cell junction remodeling, leading to endothelial barrier destabilization and permeability increase by a distinct mechanism from that initiated by VEGF.