TRPV4 channels dominant role in the temperature modulation of intrinsic contractility and lymph flow of rat diaphragmatic lymphatics

The lymphatic system drains and propels lymph by extrinsic and intrinsic mechanisms. Intrinsic propulsion depends upon spontaneous rhythmic contractions of lymphatic muscles in the vessel walls, and is critically affected by changes in the surrounding tissue like osmolarity and temperature. Lymphatics of the diaphragm display a steep change in contraction frequency in response to changes in temperature, and this, in turn, affects lymph flow. In the present work we demonstrated, in an ex vivo diaphragmatic tissue rat model, that diaphragmatic lymphatics express transient receptor potential channels of the vanilloid 4 subfamily (TRPV4), and that their blockade by both the non-selective antagonist, Ruthenium Red and by the selective antagonist, HC-067047, abolished the response of lymphatics to temperature changes. Moreover, the selective activation of TRPV4 channels by means of GSK1016790A mirrored the behavior of vessels exposed to increasing temperatures, pointing out the critical role played by these channels in sensing the temperature of the lymphatic vessels environment and thus inducing a change in contraction frequency and lymph flow.