Unravelling the role of cellular microvesicles on lymphatic vessel function

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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.