Efficient aortic lymphatic drainage is necessary for atherosclerosis regression induced by ezetimibe

Abstract

A functional lymphatic vasculature is essential for tissue fluid homeostasis, immunity, and lipid clearance. Although atherosclerosis has been linked to adventitial lymphangiogenesis, the functionality of aortic lymphatic vessels draining the diseased aorta has never been assessed and the role of lymphatic drainage in atherogenesis is not well understood. We develop a method to measure aortic lymphatic transport of macromolecules and show that it is impaired during atherosclerosis progression, whereas it is ameliorated during lesion regression induced by ezetimibe. Disruption of aortic lymph flow by lymphatic ligation promotes adventitial inflammation and development of atherosclerotic plaque in hypercholesterolemic mice and inhibits ezetimibe-induced atherosclerosis regression. Thus, progression of atherosclerotic plaques may result not only from increased entry of atherogenic factors into the arterial wall but also from reduced lymphatic clearance of these factors as a result of aortic lymph stasis. Our findings suggest that promoting lymphatic drainage might be effective for treating atherosclerosis.

Oxidatively Modified LDL Suppresses Lymphangiogenesis via CD36 Signaling

“…Furthermore, genetic disruption of lymphatic drainage using soluble vascular endothelial growth factor receptor 3 (sVGFR3) overexpression, which results in LV regression, and surgical removal of lesion-draining lymph nodes promote atherosclerosis development in hypercholesterolemic mice [ 2 , 4 , 5 ]. Consistent with this information, a recent study showed that disruption of aortic lymph flow by LV ligation stimulates atherosclerotic lesion formation [ 3 ]. The same study reported that regression of atherosclerosis induced by cholesterol lowering therapy in ApoE −/− mice requires efficient lymphatic drainage.…”

“…Atherosclerosis is a chronic inflammatory disease characterized by the influx, oxidation, and accumulation of apoB-containing lipoproteins in large and medium-sized arteries. Recent studies have demonstrated the importance of arterial lymphatic vessels (LV) in the removal of cholesterol via HDL-mediated reverse cholesterol transport, egress of inflammatory cells from the arterial wall and regulation of arterial inflammation [ 2 , 3 ]. Furthermore, genetic disruption of lymphatic drainage using soluble vascular endothelial growth factor receptor 3 (sVGFR3) overexpression, which results in LV regression, and surgical removal of lesion-draining lymph nodes promote atherosclerosis development in hypercholesterolemic mice [ 2 , 4 , 5 ].…”

Leukocyte Trafficking via Lymphatic Vessels in Atherosclerosis

“…Similar expansion of adventitial lymphatic network was also observed in hypercholesterolemic Apoe −/− mice [91,92]. The temporal and spatial assessment of lymphangiogenesis was carefully studied at various regions of the aortae in Apoe −/− and Ldlr −/− mice [86]. Adventitial lymphangiogenesis develops at later stages of plaque development and dilated lymphatic vessels were more numerous in advanced plaques.…”

“…As most mechanistic insights depend on in vivo studies using smaller mouse model, it is critical to know the exact topography of aortic lymphatic vessels in a mouse model. Using histological and imaging analysis, characterization and topographic distribution of the lymphatic vessel network in the normal mouse aorta were recently illustrated [86]. Blind-ended lymphatic vessels expressing LYVE-1, vascular endothelial growth receptor-3 (VEGFR-3), podoplanin, and prox-1 were found residing in the collagen I-rich aortic adventitia and peri-adventitial tissues of the aortic sinus (Figure 2), thoracic aorta, and abdominal aorta, while aortic arch is destitute of lymphatic vessels.…”

“…Blind-ended lymphatic vessels expressing LYVE-1, vascular endothelial growth receptor-3 (VEGFR-3), podoplanin, and prox-1 were found residing in the collagen I-rich aortic adventitia and peri-adventitial tissues of the aortic sinus (Figure 2), thoracic aorta, and abdominal aorta, while aortic arch is destitute of lymphatic vessels. Lymphatic vessels ran alongside the thoracic and abdominal aorta, having one plexus anatomically closer to the vein while another weaving in and out the adjacent periadventitial adipose tissues and encircling the arterial branches [86].…”