Unravelling the role of cellular microvesicles on lymphatic vessel function

动脉粥样硬化是加拿大死亡和发病的主要原因之一。它是由胆固醇和血管（动脉）壁上的炎症细胞的积累所驱动的，这些细胞形成了所谓的“斑块”。人们一直致力于提高高密度脂蛋白胆固醇（HDL-C，或“好胆固醇”）的循环水平，以减少斑块大小，从而降低冠状动脉疾病（CAD）的患病率。然而，提高血浆HDL-C水平的临床结果令人失望，这表明这种策略可能不会增加胆固醇动员能力或预防CAD。由于迫切需要更好地了解胆固醇清除过程，除了胆固醇向胆固醇受体（如HDL）的转变之外，我和合作者已经专注于胆固醇受体实际离开斑块的途径，并发现了调节胆固醇从动脉壁去除的一个新的先决条件：淋巴系统。由于淋巴系统——淋巴，来自拉丁语淋巴，意思是水——通常控制着大分子从组织到血液的运输，相应地，周围淋巴含有胆固醇受体，在胆固醇运输中的作用似乎是合乎逻辑的。

Atherosclerosis is one of the leading causes of mortality and morbidity in Canada. It is driven by the accumulation of cholesterol and inflammatory cells in the blood vessel (artery) wall that build up what is called a "plaque". Much effort has been directed at increasing circulating levels of high density lipoprotein cholesterol (HDL-C, or "good cholesterol") to decrease plaque size and consequently, prevalence of coronary artery disease (CAD). However, raising plasma levels of HDL-C has met with disappointing clinical outcomes, suggesting that this strategy may not lead to an increased cholesterol mobilization capacity or prevent CAD. As there is an urge to better understand the cholesterol clearance process, beyond the transition of cholesterol onto cholesterol acceptors such as HDL, collaborators and I have focused on the path cholesterol acceptors are actually taking to leave plaque, and discovered a new prerequisite player in the modulation of cholesterol removal from the artery wall: the lymphatic system. As the lymphatic system - lymph, from Latin lympha, meaning water - generally governs the transport of macromolecules from the tissues to the blood and, accordingly, peripheral lymph contains cholesterol acceptors, a role in cholesterol transport seemed logical. Based on a strong scientific background acquired in Quebec and in the US, with world-renowned experts in cardiology and immunology, my team and I now aim to unravel the mechanisms leading to this abnormal lymphatic function observed in atherosclerosis onset and progression. Our recent work suggests that this impairment is most likely precociously associated with a defect in the pumping capacity of the lymphatic vessels to propel lymph down the road. Therefore, our goal is to identify the origin of this problem by pointing out whether and how lymph composition could affect the mechanical function of the lymphatic contractile units. As plaque also accumulates certain types of proatherogenic cell fragments called "microvesicles", we will more specifically test whether these waste products are contained in lymph and how they potentially modulate the lymphatic contraction capacity. In keeping with the mission of the NSERC, we will explore the lymphatic physiology beyond the edges, with the ultimate goal of discovering new modulators of lymphatic vessel function.