Protease-activated receptor (PAR) 1 but not PAR2 or PAR4 mediates endothelium-dependent relaxation to thrombin and trypsin in human pulmonary arteries

Endothelial protease-activated receptors (PARs) may be important sensors of vascular inflammation and injury. Activation of endothelial PAR1 and PAR4 causes nitric oxide-mediated arterial smooth muscle relaxation in a number of species and PAR4 activation causes similar responses in isolated rat aor ta. However, it is unclear whether these receptors mediate such responses i n human arteries because the most potent activators of PAR1, PAR2, and PAR4 , thrombin and trypsin, cause endothelium-dependent relaxation of human cor onary arteries through a common PAR1-like receptor. This study aimed to det ermine whether this unique pharmacology of PARs in human coronary arteries extends to human pulmonary arteries. PAR1 and PAR2 mRNA and protein were de tected in human pulmonary arteries via reverse transcription polymerase cha in reaction and immunohistochemistry, respectively. PAR4 mRNA was also dete cted in human pulmonary arteries. Contracted human pulmonary artery ring se gments suspended for isometric tension measurement relaxed in a concentrati on- and endothelium-dependent manner to thrombin (0.001-0.1 U/ml), trypsin (0.01-1 U/ml), and the PAR1-activating peptide, SFLLRN (0.1-10 muM). By con trast, the PAR2- and PAR4-activating peptides, SLIGKV and GYPGQV, respectiv ely, caused neither contraction nor relaxation of precontracted human pulmo nary arteries. Relaxations to thrombin and trypsin cross-desensitized, whil e tachyphylaxis to SFLLRN abolished subsequent relaxations to both thrombin and trypsin. We conclude that human pulmonary arteries express PAR1, PAR2, and PAR4, but that only PAR1, or a PAR1-like receptor, is coupled to endot helium-dependent relaxation.