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.
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.
|Demer, Linda L; Tintut, Yin (2015) The leading edge of vascular calcification. Trends Cardiovasc Med 25:275-7|
|Zhang, Wenwu; Huang, Youliang; Wu, Yidi et al. (2015) A novel role for RhoA GTPase in the regulation of airway smooth muscle contraction. Can J Physiol Pharmacol 93:129-36|
|Ascenzi, Maria-Grazia; Lutz, Andre; Du, Xia et al. (2014) Hyperlipidemia affects multiscale structure and strength of murine femur. J Biomech 47:2436-43|
|Demer, Linda L; Tintut, Yin (2014) Inflammatory, metabolic, and genetic mechanisms of vascular calcification. Arterioscler Thromb Vasc Biol 34:715-23|
|Tintut, Yin; Demer, Linda L (2014) Effects of bioactive lipids and lipoproteins on bone. Trends Endocrinol Metab 25:53-9|
|Sallam, Tamer; Cheng, Henry; Demer, Linda L et al. (2013) Regulatory circuits controlling vascular cell calcification. Cell Mol Life Sci 70:3187-97|
|Chen, Ting-Hsuan; Hsu, Jeffrey J; Zhao, Xin et al. (2012) Left-right symmetry breaking in tissue morphogenesis via cytoskeletal mechanics. Circ Res 110:551-9|
|Li, Rongsong; Mittelstein, David; Lee, Juhyun et al. (2012) A dynamic model of calcific nodule destabilization in response to monocyte- and oxidized lipid-induced matrix metalloproteinases. Am J Physiol Cell Physiol 302:C658-65|
|Ting, Tabitha C; Miyazaki-Anzai, Shinobu; Masuda, Masashi et al. (2011) Increased lipogenesis and stearate accelerate vascular calcification in calcifying vascular cells. J Biol Chem 286:23938-49|
|Byon, Chang Hyun; Sun, Yong; Chen, Jianfeng et al. (2011) Runx2-upregulated receptor activator of nuclear factor ?B ligand in calcifying smooth muscle cells promotes migration and osteoclastic differentiation of macrophages. Arterioscler Thromb Vasc Biol 31:1387-96|
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