Protease-activated receptors in endothelial health and dysfunction

Protease-activated receptors (PARs) connect extracellular proteolytic activity to intracellular signaling in endothelial cells, placing them at the crossroads of coagulation, inflammation, and vascular stability. This review highlights recent progress in understanding endothelial PAR1-PAR4 signaling, focusing on how protease specificity, receptor interactions, and signaling bias shape endothelial responses in both health and disease.

New research shows that endothelial PAR signaling varies greatly depending on the context. PAR1 displays biased signaling based on the type of protease and cleavage site, with thrombin mainly causing barrier disruption, while activated protein C (aPC) promotes cytoprotection via β-arrestin pathways. PAR2 processes signals from coagulation and inflammatory proteases to control endothelial inflammation, vasodilation, and paracrine signaling. Once considered a passive cofactor, PAR3 is now seen as an active regulator that forms heterodimers with PAR1, allowing engineered bivalent agonists to mimic protective aPC signaling. Notably, PAR4, a low-abundance but potent endothelial receptor, activates under conditions rich in proteases, leading to cytoskeletal changes, barrier dysfunction, and thromboinflammation.

These insights reposition endothelial PARs as sophisticated sensors of the vascular protease environment. Future therapies are moving away from broad receptor blocking toward pathway-specific modulation that maintains protective signaling while reducing vascular damage, opening new avenues for precise vascular treatments.