PAR2 Regulates Cardiac Pressure and Vascular Function Through Context-Dependent Signalling Mechanisms

Proteinase-activated receptor-2 (PAR2) regulates cardiac pressure and vascular function through context-dependent mechanisms that integrate G protein-coupled receptor signalling. We investigated the baseline cardiovascular phenotype of PAR2-deficient (PAR2^-/-) mice and the acute in vivo effects of the PAR2 agonist trans-cinnamoyl-Leu-Ile-Gly-Arg-Leu-Orn-amide (tcLIGRLO). Left ventricular pressure-volume (PV) analysis revealed that PAR2^-/- mice had elevated systolic and diastolic pressures with reduced end-diastolic volumes and increased ejection fraction while maintaining stroke volume and cardiac output. Thus, PAR2 deficiency produces a pressure-dominant cardiovascular state with increased mechanical work and preserved global function. In WT mice, tcLIGRLO dose-dependently reduced cardiac pressure generation, contractility, relaxation kinetics, and stroke work, whereas these effects were absent in PAR2^-/- mice, indicating PAR2-dependent cardiac regulation. Despite these changes, global cardiac output remained largely preserved despite modest reductions in heart rate. In contrast, tcLIGRLO elicited strain-dependent vascular responses, including altered effective aortic elastance and reduced carotid blood flow in PAR2^-/- mice. Ex vivo experiments showed that tcLIGRLO-induced contraction in PAR2^-/- arteries required Gq-dependent signalling in this experimental context. These findings identify PAR2 as a context-dependent regulator of cardiac pressure and vascular tone, in which PAR2-dependent cardiac effects and PAR2-independent, Gq-mediated vascular responses reflect distinct but interacting signalling mechanisms.