Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR) is involved in vascular function

Background and Purpose Proteinase-activated receptors (PARs) and toll-like receptors (TLRs) are involved in innate immune responses. The aim of this study was to evaluate the possible cross-talk between PAR and TLR4 in vessels in physiological condition and how it varies following stimulation of TLR4 by using in vivo and ex vivo models. Experimental Approach Thoracic aortas were harvested from both naïve and endotoxaemic rats for in vitro studies. Arterial blood pressure was monitored in anaesthetized rats in vivo. LPS was used as a TLR4 agonist while PAR activating peptide (AP) was used as a PAR agonist. Aortas harvested from TLR4 mice were also used to characterize the PAR response. Key Results PAR , but not TLR4, expression was enhanced in aortas of endotoxaemic rats. PARAP-induced vasorelaxation was increased in aortic rings of LPS-treated rats. TLR4 inhibitors, curcumine and resveratrol, reduced PAR AP-induced vasorelaxation and PARAP-induced hypotension in both naïve and endotoxaemic rats. Finally, in aortic rings from TLR4 mice, the expression of PAR was reduced and the PARAP-induced vasodilatation impaired compared with those from wild-type mice and both resveratrol and curcumine were ineffective. Conclusions and Implications Cross-talk between PAR and TLR4 contributes to vascular homeostasis.