Proteinase-activated receptor 2 activation modulates guinea-pig mesenteric lymphatic vessel pacemaker potential and contractile activity.

Abstract

Lymphatic vessels rhythmically constrict to avoid fluid and protein accumulation in the interstitial space. This activity is critical during inflammation to prevent excessive oedema. Lymphatic pumping is intrinsic to the smooth muscle in the vessel wall and is due to the spontaneous occurrence of action potentials, the pacemaker of which is proposed to be spontaneous transient depolarizations (STDs). This function is highly susceptible to the fluid load and modulated by chemical agents, amongst which inflammatory mediators are important players. Activation of proteinase-activated receptors (PARs) has been involved in inflammation and affects vascular smooth muscle tone. The present study aims to investigate the role of PAR2, a member of the PAR family, in lymphatic vessel pumping. RT-PCR experiments revealed that PAR2 message is present in lymphatic vessels of the guinea-pig mesentery. Agonists of PAR2 such as trypsin and the activating peptide, SLIGRL-NH2, caused a decrease in the contractile activity of intraluminally perfused lymphatic vessels. Moreover, intracellular microelectrode recordings from isolated vessels revealed that PAR2 activation hyperpolarized the lymphatic smooth muscle membrane potential and altered STD amplitude and frequency. The decreases in constriction frequency and STD activity as well as the hyperpolarization were dependent on a functional endothelium, not affected by NO synthase or guanylyl-cyclase inhibition, but mimicked by PGE2 and iloprost and blocked by indomethacin (10 microM) and glibenclamide (1 microM). These results show that PAR2 activation alters guinea-pig lymphatic vessel contractile and electrical activity via the production of endothelium-derived cyclo-oxygenase metabolites.