Role of Lymphatic Clearance in Lipid-Induced Calcific Vasculopathy and Bone Loss

描述（由申请人提供）：尽管采取了大量的治疗干预措施，动脉粥样硬化仍然是发病和死亡的主要原因。有证据表明，美国人越来越久坐的生活方式正在损害降脂治疗的益处。人们普遍认为，脂蛋白的组织沉积和修饰会诱发炎症和动脉粥样硬化。我们和其他人现在表明血管钙化和骨质流失的机制相同。众所周知，组织间隙通常是通过淋巴循环系统的液体循环来清除的，而淋巴循环没有泵，依赖于体力活动。有趣的是，即使是轻微的体力活动（低于促进有氧能力的水平）也可以通过未知的机制减少心血管疾病。动脉粥样硬化研究的一个有前景的领域是反向胆固醇转运，其重点是将脂蛋白沉积物从动脉壁间质空间清除到循环系统中以进行肝脏清除。然而，如果久坐行为损害了淋巴循环，那么在分子水平上增强胆固醇反向转运可能不会转化为临床益处。需要综合生理学方法来补充当前逆转胆固醇转运的分子方法。我们假设增强淋巴清除可以减少脂蛋白在间质空间中的停滞，并预防血管和骨骼炎症和疾病。为了检验这一新假设，我们将开发干预措施，以最大化和最小化动脉粥样硬化和骨质疏松症小鼠模型中的淋巴流量。我们将使用三种干预措施来诱导小鼠淋巴清除率的变化：1）Lyve1 缺陷，增强基线淋巴循环，2）控制体力活动，增加淋巴流量，3）镇静剂减少淋巴流量。在具体目标 1 中，我们将通过高脂血症小鼠饮食诱导的动脉粥样硬化和血管钙化，探讨最大与最小淋巴清除率对血管疾病的影响。在具体目标 2 中，我们将利用饮食诱导的骨质疏松症，在高脂血症小鼠中探讨最大与最小淋巴清除率对骨病的影响。在这项试点研究中，我们将探索诱导淋巴流动所需的活动频率和强度水平，并测试最大化淋巴循环是否可以预防血管和骨骼疾病。这项工作的结果可能会带来一个有前景的新研究方向，对动脉粥样硬化和骨质疏松症的预防和治疗大有裨益。 公共卫生相关性：长期久坐行为会导致淋巴清除不良，可能是动脉壁甚至骨骼中脂质积累和氧化的关键机制。需要淋巴循环来清除炎症和氧化脂质，但如果没有体力活动，淋巴循环就会失败。这项研究将测试通过体力活动促进淋巴清除是否可以预防心脏和骨骼的慢性炎症性疾病，例如动脉粥样硬化和骨质疏松症。

DESCRIPTION (provided by applicant): Atherosclerosis remains a major cause of morbidity and mortality despite substantial therapeutic interventions. Evidence suggests that the ever-more sedentary lifestyle of Americans is undermining the benefits of lipid- lowering therapy. It is widely accepted that tissue deposition and modification of lipoproteins induce inflammation and atherosclerosis; we and others are now showing that the same mechanism underlies vascular calcification and bone loss. It is well known that the interstitial spaces of tissues are normally cleared by fluid circulation through the lymphatic circulatory system, and that lymphatic circulation, which has no pump, depends on physical activity. Interestingly, cardiovascular disease is reduced by even mild physical activity -- below levels that promote aerobic capacity -- through mechanisms that are not known. One promising area of atherosclerosis research is reverse cholesterol transport, which focuses on removing lipoprotein deposits from the interstitial spaces of the artery wall to the circulation for hepatic clearance. However, if sedentary behavior impairs lymphatic circulation, enhancing reverse cholesterol transport at the molecular level may not translate to clinical benefit. Integrative physiological approaches are needed to complement the current molecular approach to reverse cholesterol transport. We hypothesize that enhancing lymphatic clearance reduces stagnation of lipoproteins in the interstitial spaces and prevents vascular and bone inflammation and disease. To test this novel hypothesis, we will develop interventions to maximize and minimize lymphatic flow in a mouse model of atherosclerosis and osteoporosis. We will use three interventions to induce changes in lymphatic clearance in mice: 1) Lyve1 deficiency, which enhances baseline lymphatic circulation, 2) controlled physical activity, to increase lymphatic flow, and 3) sedatives to reduce lymphatic flow. In Specific Aim 1, we will explore the effects of maximal vs. minimal lymphatic clearance on vascular disease using diet-induced atherosclerosis and vascular calcification in hyperlipidemic mice. In Specific Aim 2, we will explore the effects of maximal vs. minimal lymphatic clearance on bone disease using diet-induced osteoporosis in hyperlipidemic mice. In this pilot study, we will explore the levels of frequency and intensity of activity required to induce lymphatic flow, and test whether maximizing lymphatic circulation prevents vascular and bone disease. Findings of this work could introduce a promising new direction of research and greatly benefit prevention and treatment of atherosclerosis and osteoporosis. PUBLIC HEALTH RELEVANCE: Prolonged sedentary behavior, which leads to poor lymphatic clearance, may be a key mechanism for accumulation and oxidation of lipids in the artery wall and even in bone. Lymphatic circulation is needed to clear inflammatory and oxidized lipids, but it fails without physical activity. This study will test whether promoting lymphatic clearance by physical activity can prevent chronic inflammatory diseases of the heart and bone such as atherosclerosis and osteoporosis.