Effects of Lipoxin A₄ on CoCl₂-Induced Angiogenesis and Its Possible Mechanisms in Human Umbilical Vein Endothelial Cells

Abstract

Lipoxin A₄ (LXA₄), a ‘stop signal’ for inflammation, is endogenously produced by eicosanoids, mainly via cell-to-cell interactions. At present, its influence on hypoxic angiogenesis, which is responsible for tumor growth and metastasis, has not been determined. Hypoxia regulates a variety of transcription factors including hypoxia-inducible factor (HIF)-1α, which plays a role in the expression of vascular endothelial growth factor (VEGF) and is considered a target for anti-angiogenic therapy. In this study, we utilized cobalt chloride (CoCl₂) to mimic hypoxia in vitro. Data suggested that LXA₄ decreased the expression and nucleus translocation of HIF-1α in a dose-dependent manner in CoCl₂-treated human umbilical vein endothelial cells (HUVEC). Furthermore, we confirmed that LXA₄ suppressed VEGF expression, tube formation and migration activity of HUVEC under hypoxia induced by CoCl₂. These results suggest that LXA₄ may have inhibitory effects on tumor angiogenesis through downregulation of the expression and nucleus translocation of HIF-1α. In summary, this study provides the first evidence for the anti-angiogenic role of LXA₄ on hypoxic human endothelial cells, which may have therapeutic value for cancer and other angiogenesis-associated diseases.

Hypoxia effects on proangiogenic factors in human umbilical vein endothelial cells: functional role of the peptide somatostatin

“…1a, the predicted length of each qPCR product was confirmed by agarose gel electrophoresis (148, 106, 92 and 60 bp which correspond to the predicted length of VEGF, VEGFR-1, VEGFR-2 and GAPDH mRNA, respectively). In agreement with previous results demonstrating that hypoxia is a potent stimulus for VEGF upregulation in HUVEC (Avouac et al 2008;Cho et al 2008;Liu et al 2009;Nilsson et al 2004;Takata et al 2008;Zheng et al 2008), we found that hypoxia caused a drastic increase in the level of the VEGF mRNA (∼163%, **P < 0.01; Fig. 1b) while we also determined a significant decrease in the expression of both VEGFR-1 (∼58%, **P<0.01; Fig.…”

“…Our study shows that hypoxia is a potent stimulus for VEGF expression and production, confirming previous findings in HUVEC (Avouac et al 2008;Cho et al 2008;Liu et al 2009;Nilsson et al 2004;Takata et al 2008;Zheng et al 2008). Hypoxia has been proposed to play an important role in the regulation of VEGF receptor expression although previous studies have yielded conflicting results.…”

“…In fact, there are studies reporting either upregulation or downregulation of VEGF receptors in hypoxic conditions (Avouac et al 2008;Gerber et al 1997;Liu et al 2009;Takata et al 2008;Waltenberger et al 1996), whereas no effects of hypoxia have been demonstrated by Nillson et al (2004). In this respect, passage-related effects on cell cultures manifest as alterations in cellular protein expression.…”

“…VEGF is one of the most potent proangiogenic factors which promotes the proliferation and migration of endothelial cells and increases vascular permeability. In human umbilical vein endothelial cells (HUVEC), which are widely used as an endothelial cell model in vitro, hypoxia increases VEGF expression and secretion (Avouac et al 2008;Cho et al 2008;Liu et al 2009;Nilsson et al 2004;Takata et al 2008;Zheng et al 2008).…”

Secalonic Acid-D Represses HIF1α/VEGF-Mediated Angiogenesis by Regulating the Akt/mTOR/p70S6K Signaling Cascade

“…We pretreated the cells with CoCl 2 , which was widely used for the induction of hypoxiainduced angiogenesis (28,29). The expression level of angiogenic factors such as HIFa, HIFb, VEGFR2, p-VEGFR2, and all the key proteins of Akt/mTOR signaling cascade was significantly enhanced in CoCl 2 -pretreated samples as compared with untreated cells (Fig.…”