Trpv4 regulation of lymphatic vascular function: Implications in metabolic syndrome

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PROJECT SUMMARY A major function of the lymphatic system is fluid transport, which is critical for fluid homeostasis, lipid transport and metabolism, and the transport of immune cells and pro-inflammatory molecules. Lymphatic vessels contract spontaneously to pump fluid, while intraluminal one-way valves ensure net forward flow. Our group and others have shown that obesity and metabolic syndrome can cause different forms of lymphatic vascular dysfunction. In fact, this connection is a dysfunction- and disease-promoting feedback loop, as lymphatic dysfunction also contributes to obesity. This suggests pharmacological improvement of lymphatic function as a potential therapeutic alternative in obesity and metabolic syndrome. Relevant to this proposal, transient receptor potential vanilloid 4 (Trpv4) channels are key regulators of vascular function, and their activity is dysregulated in various inflammatory diseases, including obesity and metabolic syndrome; however, the role of Trpv4 channels in regulating lymphatic vascular function in health and disease remains unexplored. Our preliminary studies show that overactivity of Trpv4 channels in a variety of cell types within and around the lymphatic wall is detrimental to different aspects of the function of the lymphatic vasculature, including impairment of contractility and compromised barrier function. Importantly, partial deficiency of Trpv4 channels in the lymphatic endothelium prevented significant impairment of lymphatic function upon stimulation of Trpv4 channels. Trpv4 channels have also been implicated in regulatory mechanisms of tissue fibrosis via activation of the Plasminogen Activator Inhibitor-1 (PAI-1) leading to remodeling of the extracellular matrix. PAI-1 is an important biomarker for disease, fibrosis, and inflammation. We recently showed that PAI-1 is significantly increased in the lymphatic vasculature of diet-induced obese mice; and globally deficient PAI-1 mice are significantly protected against diet-induced obesity and metabolic dysfunction; however, the underlying mechanisms remain unknown. In line with the emerging significant role of the lymphatic system in lipid metabolism, we hypothesize that, in obesity and metabolic syndrome, increased PAI-1 can be a key modulator of Trpv4 overactivity, and this is detrimental for lymphatic vascular function, which reciprocally exacerbates obesity. We propose evaluating PAI-1 as a long-term therapeutic alternative for direct or indirect modulation of Trpv4 activity. We anticipate that reducing inflammation and fibrosis via PAI-1 inhibition will decrease direct activation of Trpv4 channels in two ways, 1) by decreasing inflammatory molecules; and 2) by reducing stiffening of the extracellular matrix, and therefore decreasing stretch-mediated activation. As important regulators of inflammatory responses, dual targeting of Trpv4 and PAI-1 may offer synergistic therapeutic benefits, to be evaluated in this proposal. This project will provide fundamental information about Trpv4 channels in the regulation of lymphatic vascular function and will identify the role of lymphatic Trpv4 channels in obesity and metabolic syndrome.