Oxidatively modified ldl suppresses lymphangiogenesis via cd36 signaling

Bhupesh Singla, Hui Ping Lin, Wonmo Ahn, Joseph White, Gábor Csányi

Research output: Contribution to journalArticlepeer-review

Abstract

Arterial accumulation of plasma‐derived LDL and its subsequent oxidation con-tributes 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 iden-tified. 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 de-tected 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 dele-tion 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. Collec-tively, 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.

Original languageEnglish (US)
Article number331
Pages (from-to)1-21
Number of pages21
JournalAntioxidants
Volume10
Issue number2
DOIs
StatePublished - Feb 2021

Keywords

  • Atherosclerosis
  • CD36
  • Lymphangiogenesis
  • Native LDL
  • Oxidized LDL

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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