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

描述(由申请人提供)：动脉粥样硬化仍然是发病率和死亡率的主要原因，尽管进行了大量的治疗干预。有证据表明，美国人越来越久坐不动的生活方式正在削弱降脂疗法的好处。人们普遍认为，组织中脂蛋白的沉积和修饰会导致炎症和动脉粥样硬化；我们和其他人现在发现，血管钙化和骨丢失也是同样的机制。众所周知，组织的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--也会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很有前途的领域是胆固醇反向运输，它专注于将脂蛋白沉积从动脉壁的间质间隙移至循环中，以实现肝脏的清除。然而，如果久坐行为损害淋巴循环，在分子水平上加强胆固醇的反向运输可能不会转化为临床益处。需要综合的生理学方法来补充目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间质中脂蛋白的滞留，预防血管和骨骼炎症和疾病。为了验证这一新的假设，我们将开发干预措施，在动脉粥样硬化和骨质疏松症的小鼠模型中最大化和最小化淋巴流量。我们将使用三种干预措施来诱导小鼠淋巴清除的变化：1)LYVE1缺乏症，增强基线淋巴循环；2)受控体力活动，增加淋巴流量；3)镇静剂，减少淋巴流量。在特定的目标1中，我们将利用饮食诱导的动脉粥样硬化和高脂血症小鼠的血管钙化来探索最大和最小淋巴清除对血管疾病的影响。在特定的目标2中，我们将探索最大和最小淋巴清除对饮食诱导的骨质疏松症高脂血症小鼠骨病的影响。在这项初步研究中，我们将探索诱导淋巴流所需的活动频率和强度，并测试最大化淋巴循环是否可以预防血管和骨骼疾病。本工作的发现将为动脉粥样硬化和骨质疏松症的防治提供新的研究方向。 公共卫生相关性：长时间久坐导致淋巴清除不良，这可能是动脉壁甚至骨骼中脂质积聚和氧化的关键机制。淋巴循环是清除炎症和氧化脂质所必需的，但如果没有身体活动，淋巴循环就会失败。这项研究将测试通过体育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，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.