Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice

Abstract

BackgroundSubcutaneously injected lipid‐free apoA‐I (apolipoprotein A‐I) reduces accumulation of lipid and immune cells within the aortic root of hypercholesterolemic mice without increasing high‐density lipoprotein–cholesterol concentrations. Lymphatic vessels are now recognized as prerequisite players in the modulation of cholesterol removal from the artery wall in experimental conditions of plaque regression, and particular attention has been brought to the role of the collecting lymphatic vessels in early atherosclerosis‐related lymphatic dysfunction. In the present study, we address whether and how preservation of collecting lymphatic function contributes to the protective effect of apoA‐I.Methods and ResultsAtherosclerotic Ldlr −/− mice treated with low‐dose lipid‐free apoA‐I showed enhanced lymphatic transport and abrogated collecting lymphatic vessel permeability in atherosclerotic Ldlr −/− mice when compared with albumin‐control mice. Treatment of human lymphatic endothelial cells with apoA‐I increased the adhesion of human platelets on lymphatic endothelial cells, in a bridge‐like manner, a mechanism that could strengthen endothelial cell–cell junctions and limit atherosclerosis‐associated collecting lymphatic vessel dysfunction. Experiments performed with blood platelets isolated from apoA‐I‐treated Ldlr −/− mice revealed that apoA‐I decreased ex vivo platelet aggregation. This suggests that in vivo apoA‐I treatment limits platelet thrombotic potential in blood while maintaining the platelet activity needed to sustain adequate lymphatic function.ConclusionsAltogether, we bring forward a new pleiotropic role for apoA‐I in lymphatic function and unveil new potential therapeutic targets for the prevention and treatment of atherosclerosis.

The Suggestive Effect of Apo A, Apo B, and Apo A/Apo B on Erectile Dysfunction

“…22 Apo A might prevent atherosclerosis, and its properties might be affected by its size, sequence polymorphism, the type of lipoproteins associated with it, and the inflammatory state of the vessel wall. 23 The pathogenesis of ED is similar to that of CHD. It is due to atherosclerosis, preventing the cavernous veins fromt being adequately filled, causing erection difficultly.…”

Arterial Lymphatics in Atherosclerosis: Old Questions, New Insights, and Remaining Challenges

“…This lymphatic regression may contribute to exacerbated atherosclerosis. It has been shown that apoA-I treatment improves lymphatic transport, abolishes collecting LV permeability, and reduces aortic lipid accumulation without affecting total cholesterol levels by strengthening junctions between LECs [157]. However, no prior studies have tested whether stimulation of lymphangiogenesis or lymphatic function increases reverse cholesterol transport from atherosclerotic arteries.…”

“…Treatment of atheroprone, LDLR −/− ; hApoB 100/100 mice with VEGF-C152S, a VEGFR-3 agonist, prevents lymphatic function impairment, advocating the correlation between LDLR modulation and lymphatic function [14]. Another study from the same research group has reported improved lymphatic transport and reduced permeability of collecting LVs in LDLR −/− mice treated with lipid-free apoA-I compared to control mice [157]. The authors observed plaque regression in the thoracic aorta of apoA-I-treated mice independent of plasma and lymph cholesterol accumulation.…”

“…They concluded that early VEGF-C treatment increased contraction frequency of the collecting LVs and lymphatic transport, leading to attenuated development of atherosclerosis in Western diet-fed mice. In previous studies performed by Milasan et al [14,62,157], the authors’ determined function and permeability of dermal lymphatics including popliteal LVs, back skin, and ear LVs. Importantly, the above studies did not investigate arterial LV function which would be more relevant to atherosclerosis development as the lymphatic function can vary in different organs and tissues.…”

“…LECs express CCL21 and CCL19, which guide and help in homing of CCR7 positive mature DCs, macrophages and other immune cells to lymphatic capillaries and LNs [168,169,170]. Milasan et al investigated DC mobilization through lymphatics to draining lymph nodes, however, the authors did not examine the levels of CCL21 and CCL19, and CCR7 receptor expression on the surface of DCs [14,62,157]. It is important to consider the expression of these chemokines and receptors while evaluating lymphatic function.…”