Characterization of biosynthesis and modes of action of prostaglandin E₂ and prostacyclin in guinea pig mesenteric lymphatic vessels

Abstract

Background and purpose: Rhythmical transient constrictions of the lymphatic vessels provide the means for efficient lymph drainage and interstitial tissue fluid balance. This activity is critical during inflammation, to avoid or limit oedema resulting from increased vascular permeability, mediated by the release of various inflammatory mediators. In this study, we investigated the mechanisms by which prostaglandin E2 (PGE2) and prostacyclin modulate lymphatic contractility in isolated guinea pig mesenteric lymphatic vessels. Experimental approach: Quantitative RT-PCR was used to assess the expression of mRNA for enzymes and receptors involved in the production and action of PGE2 and prostacyclin in mesenteric collecting lymphatic vessels. Frequency and amplitude of lymphatic vessel constriction were measured in the presence of these prostaglandins and the role of their respective EP and IP receptors assessed. Key results: Prostaglandin E2 and prostacyclin decreased concentration-dependently the frequency, without affecting the amplitude, of lymphatic constriction. Data obtained in the presence of the EP4 receptor antagonists, GW627368x (1 mM) and AH23848B (30 mM) and the IP receptor antagonist CAY10441 (0.1 mM) suggest that PGE2 predominantly activates EP4, whereas prostacyclin mainly stimulates IP receptors. Inhibition of responses to either prostaglandin with H89 (10 mM) or glibenclamide (1 mM) suggested a role for the activation of protein kinase A and ATP-sensitive K + channels. Conclusions and implications: Our findings characterized the inhibition of lymphatic pumping induced by PGE2 or prostacyclin in guinea pig mesenteric lymphatics. This action is likely to impair oedema resolution and to contribute to the pro-inflammatory actions of these prostaglandins.

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

“…Our data confirm the pivotal role played by K ATP channels in regulating lymphatic pumping (25,30,39,45,52,58), as evidenced by the potent action of cromakalim to hyperpolarize lymphatic muscle and abolish the phasic contractions that mesenteric lymphatics characteristically exhibit (Fig. 2).…”

“…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.…”

“…During inflammation, the lymphatic system is critical in transporting dendritic cells, macrophages, and lymphocytes from inflamed sites to lymph nodes, as well as resolving the associated edema (57). It has been noted that the increased interstitial fluid causes an increase in lymphatic contractility and lymph flow and that the various inflammatory mediators present during an inflammatory episode can cause alterations in lymphatic function (3,45,56).…”

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

“…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.…”

Mesenteric lymphatic vessels adapt to mesenteric venous hypertension by becoming weaker pumps

“…In particular, prostaglandin (PGE 2 ) and prostacyclin (PGI 2 ) have been reported to relax lymphatic muscle and inhibit pumping of both bovine and guinea pig mesenteric lymphatic vessels in a concentration-dependent manner (8,42,55). PGE 2 and PGI 2 have been proposed as mediators of the compromised contractility of mesenteric lymphatic vessels observed in an animal model of intestinal inflammation, because COX inhibitors partially restore contractility (8,42,55). In addition to responses to exogenous prostanoids, lymphatic vessels have been reported to be capable of producing PGE 2 and PGI 2 (42).…”