Involvement of TRPM4 in Stretch‐Induced Modulation of Lymphatic Pumping

Abstract

Rhythmic and phasic contractions of collecting lymphatic vessels are critically involved in tissue fluid homeostasis and immune response. This contractile activity, or lymphatic pumping, is exquisitely regulated by luminal fluid pressure. However, the molecular contributors of stretch‐induced lymphatic pumping are not known. Some members of the TRP channel family, in particular TRPM4,have been shown to respond to stretch or pressure and to contribute to myogenic vasoconstriction and vascular response to stretch.Using pressure myography, electrophysiology, pharmacology and quantitative real‐time PCR, we tested the hypothesis that TRPM4 is also a major contributor of the lymphatic vessel response to stretch.We demonstrated the expression of TRPM4 mRNA in rat mesenteric lymphatic vessels and showed that the contraction frequency of the vessels pressurized at 3 mmHg was inhibited in a concentration‐dependent manner by the TRPM4 blocker 9‐phenanthrol (IC50=1.2 µM). The blocker (10 µM) also inhibited the pressure‐induce increase in contraction frequency in an endothelium‐independent manner and caused a hyperpolarization of the lymphatic muscle. These findings suggest an important role for TRPM4 in the ability of lymphatic vessels to adapt their contractile activity to changes in intraluminal lymph pressure.