Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1alpha in vascular smooth muscle cells.
Hypoxia-inducible factor-1 (HIF-1) controls the expression of a number of genes such as vascular endothelial growth factor (VEGF) and Erythropoietin in low oxygen conditions (hypoxia). VEGF is strongly induced at both the mRNA and protein expression level by a number of hormones and growth factors in vascular smooth muscle cells (VSMC) independently of the oxygen environment. However, the role of HIF-1alpha in this induction has not been studied. We report here that HIF-1alpha protein levels are strongly increased by fetal calf serum in quiescent VSMC. More interestingly, Angiotensin II (Ang II), thrombin, platelet-derived growth factor, and other hormones can also increase HIF-1alpha in VSMC to levels that are substantially more elevated than the hypoxic treatment. HIF-1alpha induced by Ang II is located in the nucleus, binds to the hypoxic response element, and is transcriptionally active. The induction of HIF-1alpha by hormones is mediated through the production of reactive oxygen species (ROS), since it can be blocked by the ROS inhibitors, diphenyleneiodonium and catalase. Finally, strong induction of VEGF mRNA by Ang II can also be inhibited by these ROS inhibitors. These results implicate HIF-1alpha and HIF-1-dependent transcriptional activity in the induction of VEGF expression after agonist stimulation and define novel hypoxia-independent mechanisms that should play a major role in vascular remodeling.
Richard
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Institute of Signaling, Developmental Biology and Cancer Research, UMR CNRS 6543, Centre Antoine Lacassagne, 33 Avenue Valombrose, 06189 Nice, France. drichard@unice.fr
Berra
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Pouyssegur
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D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000819:agonists / Q000096:biosynthesis*; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines / Q000096:biosynthesis; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D009687:Nuclear Proteins / Q000819:agonists / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D017931:DNA Primers; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000804:Angiotensin II