Role of endothelial cell-derived angptl2 in vascular inflammation leading to endothelial dysfunction and atherosclerosis progression

Eiji Horio, Tsuyoshi Kadomatsu, Keishi Miyata, Yasumichi Arai, Kentaro Hosokawa, Yasufumi Doi, Toshiharu Ninomiya, Haruki Horiguchi, Motoyoshi Endo, Mitsuhisa Tabata, Hirokazu Tazume, Zhe Tian, Otowa Takahashi, Kazutoyo Terada, Motohiro Takeya, Hiroyuki Hao, Nobuyoshi Hirose, Takashi Minami, Toshio Suda, Yutaka KiyoharaHisao Ogawa, Koichi Kaikita, Yuichi Oike

Research output: Contribution to journalArticlepeer-review

127 Citations (Scopus)


Objective-cardiovascular disease (CVD), the most common morbidity resulting from atherosclerosis, remains a frequent cause of death. Efforts to develop effective therapeutic strategies have focused on vascular inflammation as a critical pathology driving atherosclerosis progression. Nonetheless, molecular mechanisms underlying this activity remain unclear. Here, we ask whether angiopoietin-like protein 2 (Angptl2), a proinflammatory protein, contributes to vascular inflammation that promotes atherosclerosis progression. Approach and results-Histological analysis revealed abundant Angptl2 expression in endothelial cells and macrophages infiltrating atheromatous plaques in patients with cardiovascular disease. Angptl2 knockout in apolipoprotein E-deficient mice (ApoE-/-/Angptl2-/-) attenuated atherosclerosis progression by decreasing the number of macrophages infiltrating atheromatous plaques, reducing vascular inflammation. Bone marrow transplantation experiments showed that Angptl2 deficiency in endothelial cells attenuated atherosclerosis development. Conversely, ApoE-/- mice crossed with transgenic mice expressing Angptl2 driven by the Tie2 promoter (ApoE-/-/Tie2-Angptl2 Tg), which drives Angptl2 expression in endothelial cells but not monocytes/macrophages, showed accelerated plaque formation and vascular inflammation because of increased numbers of infiltrated macrophages in atheromatous plaques. Tie2-Angptl2 Tg mice alone did not develop plaques but exhibited endothelium-dependent vasodilatory dysfunction, likely because of decreased production of endothelial cell-derived nitric oxide. Conversely, Angptl2-/- mice exhibited less severe endothelial dysfunction than did wild-type mice when fed a high-fat diet. In vitro, Angptl2 activated proinflammatory nuclear factor-κB signaling in endothelial cells and increased monocyte/macrophage chemotaxis. Conclusions-Endothelial cell-derived Angptl2 accelerates vascular inflammation by activating proinflammatory signaling in endothelial cells and increasing macrophage infiltration, leading to endothelial dysfunction and atherosclerosis progression.

Original languageEnglish
Pages (from-to)790-800
Number of pages11
JournalArteriosclerosis, thrombosis, and vascular biology
Issue number4
Publication statusPublished - Apr 2014

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine


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