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 PAR 2 , a member of the PAR family, in lymphatic vessel pumping. RT-PCR experiments revealed that PAR 2 message is present in lymphatic vessels of the guinea-pig mesentery. Agonists of PAR 2 such as trypsin and the activating peptide, SLIGRL-NH 2 , caused a decrease in the contractile activity of intraluminally perfused lymphatic vessels. Moreover, intracellular microelectrode recordings from isolated vessels revealed that PAR 2 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 PGE 2 and iloprost and blocked by indomethacin (10 µM) and glibenclamide (1 µM). These results show that PAR 2 activation alters guinea-pig lymphatic vessel contractile and electrical activity via the production of endothelium-derived cyclo-oxygenase metabolites.

Electrophysiological Properties of Rat Mesenteric Lymphatic Vessels and their Regulation by Stretch

“…This contrasts with data obtained in unstretched vessels, where administration of the two inhibitors markedly depolarized Vm (11 -2 mV, n = 4) and increased AP frequency (Fig. 3D) 11,20 Membrane potential responses to changes in preload…”

“…11,[20][21][22] We assessed the integrity of the endothelium in the wire-myograph-mounted vessels by measuring Vm and contraction frequency while nitric oxide synthases and cyclooxygenases were pharmacologically inhibited. In the 68 VON DER WEID ET AL.…”

“…In line with their vasodilatory/relaxing actions typically observed in other smooth muscles, nitric oxide and prostanoids, such as prostaglandin E 2 and prostacyclin, cause the lymphatic muscle to hyperpolarize and the pumping activity to slow down. 17,20,22,28,29 Endothelium-derived thromboxane A 2 , on the other hand, induces a depolarization as well as an increase in electrical activity (STDs and APs) and lymphatic vessel contraction frequency. 11,[30][31][32] We confirmed that, in wire-myograph-mounted vessels, endothelial function was compromised, as contractile and Vm responses were not affected by treatment with nitric oxide synthase and cyclooxygenase inhibitors, while the same inhibitors depolarized the Vm in unstretched vessels by about 10 mV.…”

Presence of Granulomas in Mesenteric Lymph Nodes Is Associated with Postoperative Recurrence in Crohnʼs Disease

“…The formation of granulomas in MLN may lead to lymphatic obstruction or merely reflect a fundamentally different pathogenesis of this subset of CD with granulomatous inflammation in MLN. In fact, a congenital failure of primary lymphatic valves may lead to edema and inflammation in CD, 58 whereas the relief of intestinal lymph congestion was shown to improve microscopic inflammation. 59 In addition to granuloma-obstructed lymphatics, increased lymphatic vessel density has been observed in patients with CD.…”

Involvement of the NO-cGMP-KATP channel pathway in the mesenteric lymphatic pump dysfunction observed in the guinea pig model of TNBS-induced ileitis

“…improvement of pumping with indomethacin reported in the same TNBS model (60) strongly suggest a role for products of arachidonic acid metabolism. Prostacyclin and prostaglandin E 2 (PGI 2 and PGE 2 ) have been directly associated with lymphatic pumping inhibition in the same mesenteric preparation (8,45). Action of these mediators could further explain the incomplete effect of 1400W in restoring contractile activity in vessels from TNBS-treated animals.…”