Castorena-Gonzalez Jorge A
Department of Pharmacology, School of Medicine, Tulane University, New Orleans, LA, United States.
Front Pharmacol. 2022 Mar 4;13:823266. doi: 10.3389/fphar.2022.823266. eCollection 2022.
A two-way connection between obesity and lymphatic dysfunction has now been established. Clinical studies have demonstrated that obesity significantly increases the risk for developing secondary lymphedema. Using animal-models, obesity and metabolic syndrome have been linked to different aspects of lymphatic structural abnormalities and lymphatic dysfunction, including impaired contractility, impaired flow-mediated responses, impaired fluid transport, as well as increased permeability, and abnormal dendritic cell migration among others. Dysfunction of lymphatic valves is a main form of lymphatic dysfunction, known to result in severe edematous phenotypes; however, the extent of lymphatic valve deficiency in secondary lymphedema, including obesity-induced lymphedema, remains unknown. Therefore, the aims of the present study were 1) to determine whether western diet-induced obesity results in lymphatic valve dysfunction, and 2) to determine whether lymphatic valve dysfunction in western diet-induced obesity results from the diet itself, or as a consequence of the metabolic alterations induced by the diet. First, we quantitatively assessed and compared valve function in isolated popliteal and mesenteric collecting lymphatic vessels from control and western diet-induced obese C57BL/6J (WT) mice. Feeding a western diet for 14 weeks induced obesity and elevated plasma glucose and cholesterol levels when compared to controls. The function of lymphatic valves in popliteal lymphatics was not affected by diet-induced obesity; however, significant back-leak of pressure was observed in mesenteric lymphatic valves. Dysfunctional, leaky valves from obese animals also required significantly higher adverse pressure to trigger valve closure. Importantly, when subjected to treatment with a western diet, globally deficient PAI-1 mice were significantly protected against metabolic dysfunction and displayed fully functional, competent mesenteric lymphatic valves. In conclusion, our findings show for the first time that, in association with the metabolic alterations induced by the western diet, lymphatic valve dysfunction can be a critical component of obesity-induced lymphedema.
肥胖与淋巴功能障碍之间的双向联系现已确立。临床研究表明，肥胖会显著增加继发性淋巴水肿的发病风险。利用动物模型，已将肥胖和代谢综合征与淋巴结构异常和淋巴功能障碍的不同方面联系起来，包括收缩性受损、血流介导反应受损、液体运输受损、通透性增加以及树突状细胞迁移异常等。淋巴管瓣膜功能障碍是淋巴功能障碍的主要形式，已知会导致严重的水肿表型；然而，继发性淋巴水肿（包括肥胖诱导的淋巴水肿）中淋巴管瓣膜缺陷的程度仍不清楚。因此，本研究的目的是：1）确定西式饮食诱导的肥胖是否会导致淋巴管瓣膜功能障碍；2）确定西式饮食诱导的肥胖中淋巴管瓣膜功能障碍是由饮食本身引起的，还是由饮食诱导的代谢改变导致的。首先，我们定量评估并比较了来自对照和西式饮食诱导的肥胖C57BL/6J（WT）小鼠的分离腘窝和肠系膜集合淋巴管中的瓣膜功能。与对照组相比，喂食西式饮食14周会导致肥胖，并使血浆葡萄糖和胆固醇水平升高。饮食诱导的肥胖并未影响腘窝淋巴管中淋巴管瓣膜的功能；然而，在肠系膜淋巴管瓣膜中观察到明显的压力反向渗漏。肥胖动物功能失调、渗漏的瓣膜也需要显著更高的负压来触发瓣膜关闭。重要的是，当接受西式饮食治疗时，全身性PAI - 1缺陷小鼠能显著预防代谢功能障碍，并显示出功能完全正常的肠系膜淋巴管瓣膜。总之，我们的研究结果首次表明，与西式饮食诱导的代谢改变相关，淋巴管瓣膜功能障碍可能是肥胖诱导的淋巴水肿的关键组成部分。
