title: Macrophages transmit potent proangiogenic effects of oxLDL in vitro and in vivo involving HIF-1α activation: a novel aspect of angiogenesis in atherosclerosis.
abstract: Neovascularization has been linked to the progression and vulnerability of atherosclerotic lesions. Angiogenesis is increased in lipid-rich plaque. Hypoxia-inducible factor alpha (HIF-1α) 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-1α in monocytes in a hypoxia-independent fashion. We hypothesized that HIF-1α 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-1α 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-1α and VEGF in monocyte-macrophages and significantly increased tube formation in co-cultured endothelial cells. HIF-1α inhibition reversed this effect. Second, we demonstrated a direct proangiogenic effect of oxLDL in an in vivo angiogenesis assay. Again, HIF-1α inhibition abrogated the proangiogenic effect of oxLDL. Third, in a rabbit atherosclerosis model, we studied the effect of dietary lipid lowering on arterial HIF-1α and VEGF expression. The administration of low-lipid diet significantly reduced the expression of both HIF-1α 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-1α pathway.
authors: The Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY 10029, USA. randolph.hutter@mssm.edu
authors: Randolph
authors: R
authors: Hutter
authors: Walter S
authors: WS
authors: Speidl
authors: Carolina
authors: C
authors: Valdiviezo
authors: Bernhard
authors: B
authors: Sauter
authors: Roberto
authors: R
authors: Corti
authors: Valentin
authors: V
authors: Fuster
authors: Juan J
authors: JJ
authors: Badimon
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000178:diet therapy / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D018920:Coculture Techniques; D018752:Diet, Fat-Restricted; D004195:Disease Models, Animal; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D019899:Paracrine Communication; D011817:Rabbits; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008077:Lipoproteins, LDL; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C099252:oxidized low density lipoprotein
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