Lymphatic vessel function in atherosclerosis
Atherosclerosis is driven by the accumulation of cholesterol in the arterial wall, which triggers an inappropriate immune response in which macrophages play an important role. It has now been shown that the lymphatic vessels play an important role in reverse cholesterol transport (Martel et al. JCI 2013). The overall objective of my Master internship was to better characterize lymphatic dysfunction associated with atherosclerosis, studying closely the physiological and temporal origin of this pathological feature. Our approach was to study, from the initiation of atherosclerosis to the progression of the atherosclerotic lesion, the physiology of the two main components that form the lymphatic vessels: the lymphatic capillaries and collectors. Using a mouse model that closely resembles human atherosclerosis (Ldlr-/-; hApoB100+/+) we have demonstrated that lymphatic dysfunction is present before the onset of atherosclerosis, and that this dysfunction is primarily associated with a defect in the collecting vessels, thereby limiting the lymph transport from peripheral tissues to the blood. In addition, we have clearly demonstrated, for the first time to our knowledge, the presence of the LDL receptor on lymphatic endothelial cells. Our subsequent work shows that this reduction in lymph flow could be due to the absence of the LDL receptor, and that lymphatic transport can be restored by systemic injections of VEGF (vascular endothelial growth factor) –C. These results suggest that the functional characterization of the pumping capacity of the collecting vessels would be a prerequisite for the understanding of the interactions between the function of the lymphatic system and the progression of atherosclerosis. Altogether, our work unveils new potential therapeutic targets for the prevention and treatment of atherosclerosis.
Inflammation Atherosclerosis Lymphatic vessels Lymphatic endothelial cells Lymphatic smooth muscle cells Lipoproteins Cellular transport Inflammation