COX-talk: Communication between TRPV4 channels and prostanoids in lymphatic vessel contractile response to flow.
Date
2023-07
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Abstract
The proper phasic contractility of collecting lymphatic vessels (CLVs) is critical for lymph propulsion, and it requires a tight communication between the lymphatic endothelium and surrounding smooth muscle. CLVs can sense mechanical stimuli such as pressure and shear stress generated by luminal lymph flow, which modulates their contractile function through the production of vasoactive molecules, including nitric oxide and prostanoids. Although shear stress is a vital regulator of CLV contractility, the mechanisms involved in shear sensing and the role of prostanoids in lymphatic contractile motion are not well understood. In this study, we aimed to investigate the role of the mechanosensor-transient receptor potential vanilloid 4 (TRPV4) in the crosstalk between endothelium and smooth muscle prostanoids in lymphatic vessels. Using pressure myography, we assessed the ability of rat mesenteric CLVs to respond to induced unidirectional flow by increasing the pressure gradients (1, 5, and 9 cm H2O) across the vessel. We determined the involvement of TRPV4 and cyclooxygenase (COX) through selective pharmacological inhibition of TRPV4 with GSK2193874 (GSK219), COX-1 with SC560, and COX-2 with NS398. Our data indicate that high lymph flow reduces the CLV contraction frequency in a time dependent manner. Dilatory mechanisms in response to flow are endothelial, TRPV4 channel, and COX-1-dependent. Furthermore, we found that the production of thromboxane prostanoid (TP) receptor agonists are responsible for the restoration of contraction frequency over time. Selective inhibition of the TP receptor with SQ-29,458 successfully maintains a flow-dependent contractile frequency loss in CLVs. Our findings demonstrate the expression of functional TRPV4 channels in rat mesenteric CLVs. We show that the activation of TRPV4 channels in the lymphatic endothelium induces the production of both dilatory and contractile prostanoids to regulate lymphatic pumping in response to flow. These results provide new insights into the complex regulatory mechanisms involved in the shear sensing and prostanoid-mediated crosstalk between the lymphatic endothelium and smooth muscle. Understanding the regulation of lymphatic contractility is essential for the development of therapies for lymphatic-related diseases, such as lymphedema and cancer metastasis.
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Keywords
Lymphatic, Pharmacology, Physiology, Vascular function
Citation
Brothers, P. (2023). COX-talk: communication between TRPV4 channels and prostanoids in lymphatic vessel contractile response to flow (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.