Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice
Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice
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DOI：
10.1172/jci63685
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发表时间：
2013-04-01
影响因子：
15.9
通讯作者：
Randolph, Gwendalyn J.
中科院分区：
文献类型：
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作者：
Martel, Catherine;Li, Wenjun;Randolph, Gwendalyn J.
胆固醇逆向转运（RCT）是指HDL颗粒（HDL-C）上的胆固醇从血管外组织动员到血浆中，最终用于粪便排泄。关于HDL-C如何离开外周组织到达血浆的知之甚少。我们首先使用了2种皮肤淋巴引流中断的模型（1种是手术模型，另一种是遗传模型）来定量追踪在阻塞或缺失的淋巴管上游注射负载[H-3]胆固醇的巨噬细胞后的随机对照试验。巨噬细胞RCT在两种模型中均明显受损，即使在血管渗漏部位也是如此。抑制RCT的下游的巨噬细胞的胆固醇流出，因为巨噬细胞流出的荧光胆固醇类似物（BODIPY胆固醇）不改变受损的淋巴引流。接下来，我们研究了RCT是否是由来自主动脉壁的淋巴管介导的，方法是用[H-2]（6）标记的胆固醇加载供体动脉粥样硬化Apoe缺陷小鼠的动脉，并将这些动脉手术移植到受体Apoe缺陷小鼠体内，受体Apoe缺陷小鼠用抗VEGFR 3抗体治疗以阻断淋巴再生或用对照抗体治疗以允许这种再生。[H-2]-胆固醇保留在抗-VEGFR 3处理的小鼠的睾丸中。因此，淋巴管途径对于多个组织（包括主动脉壁）的RCT至关重要。这些结果表明，在逆转动脉粥样硬化的治疗中，支持淋巴转运功能可能有助于胆固醇的清除。
Reverse cholesterol transport (RCT) refers to the mobilization of cholesterol on HDL particles (HDL-C) from extravascular tissues to plasma, ultimately for fecal excretion. Little is known about how HDL-C leaves peripheral tissues to reach plasma. We first used 2 models of disrupted lymphatic drainage from skin - 1 surgical and the other genetic - to quantitatively track RCT following injection of [H-3]-cholesterol-loaded macrophages upstream of blocked or absent lymphatic vessels. Macrophage RCT was markedly impaired in both models, even at sites with a leaky vasculature. Inhibited RCT was downstream of cholesterol efflux from macrophages, since macrophage efflux of a fluorescent cholesterol analog (BODIPY-cholesterol) was not altered by impaired lymphatic drainage. We next addressed whether RCT was mediated by lymphatic vessels from the aortic wall by loading the aortae of donor atherosclerotic Apoe-deficient mice with [H-2](6)-labeled cholesterol and surgically transplanting these aortae into recipient Apoe-deficient mice that were treated with anti-VEGFR3 antibody to block lymphatic regrowth or with control antibody to allow such regrowth. [H-2]-Cholesterol was retained in aortae of anti-VEGFR3-treated mice. Thus, the lymphatic vessel route is critical for RCT from multiple tissues, including the aortic wall. These results suggest that supporting lymphatic transport function may facilitate cholesterol clearance in therapies aimed at reversing atherosclerosis.