Oxidatively Modified LDL Suppresses Lymphangiogenesis via CD36 Signaling

Abstract

Arterial accumulation of plasma-derived LDL and its subsequent oxidation contributes to atherosclerosis. Lymphatic vessel (LV)-mediated removal of arterial cholesterol has been shown to reduce atherosclerotic lesion formation. However, the precise mechanisms that regulate LV density and function in atherosclerotic vessels remain to be identified. The aim of this study was to investigate the role of native LDL (nLDL) and oxidized LDL (oxLDL) in modulating lymphangiogenesis and underlying molecular mechanisms. Western blotting and immunostaining experiments demonstrated increased oxLDL expression in human atherosclerotic arteries. Furthermore, elevated oxLDL levels were detected in the adventitial layer, where LV are primarily present. Treatment of human lymphatic endothelial cells (LEC) with oxLDL inhibited in vitro tube formation, while nLDL stimulated it. Similar results were observed with Matrigel plug assay in vivo. CD36 deletion in mice and its siRNA-mediated knockdown in LEC prevented oxLDL-induced inhibition of lymphangiogenesis. In addition, oxLDL via CD36 receptor suppressed cell cycle, downregulated AKT and eNOS expression, and increased levels of p27 in LEC. Collectively, these results indicate that oxLDL inhibits lymphangiogenesis via CD36-mediated regulation of AKT/eNOS pathway and cell cycle. These findings suggest that therapeutic blockade of LEC CD36 may promote arterial lymphangiogenesis, leading to increased cholesterol removal from the arterial wall and reduced atherosclerosis.

Leukocyte Trafficking via Lymphatic Vessels in Atherosclerosis

“…However, manipulating VEGFR-3/VEGF-C signaling did not affect atherosclerotic plaque size and plasma cholesterol level. Oxidized LDL may also alter the growth of adventitial lymphatic vessels during atherosclerosis by acting on lymphatic endothelial cells through a CD36-dependent mechanism [93].…”

On vasa vasorum: A history of advances in understanding the vessels of vessels

“…Lymphatic vessels mediate the removal of oxidized LDL, thus reducing atherosclerotic lesion formation. Human lymphatic-derived endothelial cells exposed to oxidized LDL exhibit reduced angiogenic activity in vitro and neovessel formation in vivo via CD36 receptor–mediated signaling ( 109 ). Whether this signaling axis may be exploited for therapeutic benefit in atherosclerotic patients would be an advantageous line of inquiry.…”

Oxidized LDLs as Signaling Molecules

“…The removal of oxidized lipids operated by the lymphatic vessels seems to play a significant anti-atherogenic role, although the precise mechanism remains to be identified. A very recent study demonstrated that, in human atherosclerotic arteries, oxLDLs especially accumulate in the adventitial layer, which is particularly rich in lymphatic vessels [ 139 ]. Treatment of human lymphatic endothelial cells with oxLDLs inhibited the in vitro tube formation, an effect that was prevented by siRNA-mediated knockdown of CD36 [ 139 ].…”

“…A very recent study demonstrated that, in human atherosclerotic arteries, oxLDLs especially accumulate in the adventitial layer, which is particularly rich in lymphatic vessels [ 139 ]. Treatment of human lymphatic endothelial cells with oxLDLs inhibited the in vitro tube formation, an effect that was prevented by siRNA-mediated knockdown of CD36 [ 139 ].…”