Abstract 569: Lymphatic Function Is Impaired Before Atherosclerosis Onset in a Model of Atherosclerosis-prone Mice

Abstract

Introduction: Macrophages and cholesterol are the two main constituents driving the inflammatory response that characterizes atherosclerosis. In a recent study, the lymphatic system has been identified as a novel prerequisite player in the removal of cholesterol out of the atherosclerotic lesion. It has been shown that without a functional lymphatic network, cholesterol gets trapped in the artery wall. The lymphatic vessels are composed of two main components, namely the absorptive capillaries, responsible for the uptake of the cells, molecules and fluid, and the collecting vessels, characterized by pumping units (lymphangions) that are propelling the lymphatic content toward the blood circulation in a unidirectional manner. The relative roles of the lymphatic capillaries and collectors in the context of atherosclerotic disease are still unclear. Methods and results: Lymphatic function has been evaluated in 3-month old atherosclerosis-prone (LDLR-/-; hApoB100+/+, also called ATX mice), LDLR-/-, atherosclerosis-protected (PCSK9-/- mice, deficient in a convertase that induces the degradation of the LDL receptor) and wild-type (WT) mice. Our preliminary data show that, like LDLR-/- mice, pre-atherosclerotic ATX mice exhibit impaired lymphatic cellular transport. Immunohistochemistry and immunofluorescence imaging portrays a relatively normal number of sprouting and diameter of lymphatic vessel capillaries in the adventitial layer of the aortic sinus and in the skin dermis of ATX mice compared to WT or PCSK9-/- animals. Conclusions: Our preliminary results suggest that lymphatic transport is impaired even before the onset of atherosclerosis, and that i) the LDLR is associated with lymphatic vessel function, and that ii) the collecting lymphatic vessels are most likely responsible for the impairment in lymphatic dysfunction in LDLR-/- and ATX mice. These preliminary results suggest that characterizing the functional pumping capacity of the collecting vessels would be a prerequisite in understanding the interplay between atherosclerosis progression and lymphatic transport. We hope that in the long run we will be able to identify new therapeutic targets to enhance lymphatic transport and ultimately limit atherosclerosis progression.