Macrophages Transmit Potent Proangiogenic Effects of oxLDL In Vitro and In Vivo Involving HIF-1α Activation: a Novel Aspect of Angiogenesis in Atherosclerosis

被引:60
|
作者
Hutter, Randolph [1 ,3 ]
Speidl, Walter S. [1 ]
Valdiviezo, Carolina [1 ]
Sauter, Bernhard [2 ]
Corti, Roberto [1 ]
Fuster, Valentin [1 ]
Badimon, Juan J. [1 ]
机构
[1] Mt Sinai Sch Med, Cardiovasc Inst, New York, NY 10029 USA
[2] Mt Sinai Sch Med, Inst Gene Therapy & Mol Med, New York, NY 10029 USA
[3] Mt Sinai Sch Med, Cardiovasc Res Labs, New York, NY 10029 USA
关键词
Atherosclerosis; Lipids; Angiogenesis; Inflammation; LOW-DENSITY-LIPOPROTEIN; ENDOTHELIAL-GROWTH-FACTOR; CORONARY-ARTERY-DISEASE; OXIDATIVE MODIFICATION; TRANSCRIPTION FACTOR; PLAQUE REGRESSION; FACTOR EXPRESSION; PROGENITOR CELLS; TISSUE FACTOR; OXIDIZED LDL;
D O I
10.1007/s12265-013-9469-9
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Neovascularization has been linked to the progression and vulnerability of atherosclerotic lesions. Angiogenesis is increased in lipid-rich plaque. Hypoxia-inducible factor alpha (HIF-1 alpha) is a key transcriptional regulator responding to hypoxia and activating genes, which promote angiogenesis, among them vascular endothelial growth factor (VEGF). Oxidized low-density lipoprotein (oxLDL) is generated in lipid-rich plaque by oxidative stress. It triggers an inflammatory response and was traditionally thought to inhibit endothelial cells. New data, however, suggest that oxLDL can activate HIF-1 alpha in monocytes in a hypoxia-independent fashion. We hypothesized that HIF-1 alpha activation in monocyte-macrophages could transmit proangiogenic effects of oxLDL linking hyperlipidemia, inflammation, and angiogenesis in atherosclerosis. First, we examined the effect of oxLDL on HIF-1 alpha and VEGF expression in monocyte-macrophages and on their proangiogenic effect on endothelial cells in vitro in a monocyte-macrophage/endothelial co-culture model. OxLDL strongly induced HIF-1 alpha and VEGF in monocyte-macrophages and significantly increased tube formation in co-cultured endothelial cells. HIF-1 alpha inhibition reversed this effect. Second, we demonstrated a direct proangiogenic effect of oxLDL in an in vivo angiogenesis assay. Again, HIF-1 alpha inhibition abrogated the proangiogenic effect of oxLDL. Third, in a rabbit atherosclerosis model, we studied the effect of dietary lipid lowering on arterial HIF-1 alpha and VEGF expression. The administration of low-lipid diet significantly reduced the expression of both HIF-1 alpha and VEGF, resulting in decreased plaque neovascularization. Our data point to oxLDL as a proangiogenic agent linking hyperlipidemia, inflammation, and angiogenesis in atherosclerosis. This effect is dependent on macrophages and, at least in part, on the induction of the HIF-1 alpha pathway.
引用
收藏
页码:558 / 569
页数:12
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