Trpv4 regulation of lymphatic vascular function: Implications in metabolic syndrome

项目总结 淋巴系统的一个主要功能是液体运输，这对液体动态平衡、脂质运输至关重要。 和新陈代谢，以及免疫细胞和促炎分子的运输。淋巴管收缩 自动泵送流体，而腔内单向阀确保净向前流动。我们的团队和其他人 研究表明，肥胖和代谢综合征可导致不同形式的淋巴管功能障碍。 事实上，这种联系是一个功能障碍和促进疾病的反馈环，就像淋巴功能障碍一样 会导致肥胖。这表明药物对淋巴功能的改善是一种潜在的 肥胖症和代谢综合征的替代疗法。与这一提议相关的是，瞬时受体电位 香草素-4(TRPV4)通道是血管功能的关键调节因子，其活性在多种环境中都处于失调状态 炎症性疾病，包括肥胖和代谢综合征；然而，TRPV4通道在 在健康和疾病中调节淋巴管功能仍未被探索。我们的初步研究 表明在淋巴管壁内和周围的各种类型的细胞中TRPV4通道过度活跃 对淋巴管系统功能的不同方面有害的，包括收缩能力的损害 和受损的屏障功能。重要的是，淋巴管内皮细胞中TRPV4通道的部分缺陷 防止了刺激TRPV4通道时淋巴功能的显著损害。TRPV4频道有 还通过激活纤溶酶原激活物参与了组织纤维化的调节机制 抑制物-1(PAI-1)导致细胞外基质重塑。PAI-1是疾病的重要生物标志物， 纤维化和炎症。我们最近发现，PAI-1在淋巴管系统中显著增加 饮食诱导的肥胖小鼠；和全球缺乏PAI-1的小鼠对饮食诱导的显著保护 肥胖和代谢功能障碍；然而，潜在的机制仍不清楚。符合 淋巴系统在脂代谢中的重要作用正在显现，我们假设，在肥胖和 代谢综合征，PAI-1的增加可能是TRPV4过度活性的关键调节器，这是 对淋巴血管功能不利，反过来会加剧肥胖。我们建议 评价PAI-1作为直接或间接调节TRPV4活性的长期治疗替代方案。我们 预计通过抑制PAI-1来减轻炎症和纤维化将减少TRPV4的直接激活 通过两种途径，1)通过减少炎症分子；2)通过减少细胞外僵硬 基质，因此减少了拉伸介导的激活。作为炎症反应的重要调节者， TRPV4和PAI-1的双重靶向可能提供协同治疗益处，将在本提案中进行评估。 该项目将提供有关TRPV4通道在淋巴管调节中的基本信息 并将确定淋巴TRPV4通道在肥胖和代谢综合征中的作用。

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.