title: Hypoxia-inducible factor-3α promotes angiogenic activity of pulmonary endothelial cells by repressing the expression of the VE-cadherin gene.
abstract: The variants of the hypoxia-inducible factor-3α gene HIF-3α and NEPAS are known to repress the transcriptional activities driven by HIF-1α and HIF-2α. Although NEPAS has been shown to play an important role in vascular remodeling during lung development, little is known about the roles of HIF-3α in adult lung function. Here, we examined pulmonary endothelial cells (ECs) isolated from wild-type (WT) and HIF-3α functional knockout (KO) mice. The expression levels of angiogenic factors (Flk1, Ang2 and Tie2) were significantly greater in the HIF-3α KO ECs than those in the WT ECs irrespective of oxygen tension. However, the HIF-3α KO ECs showed impaired proliferative and angiogenic activities. The impaired EC function was likely due to the excess vascular endothelial (VE)-cadherin, an inhibitor of Flk1/PI3 kinase/Akt signaling, as treatment of the cells to a neutralizing antibody partly restored the phenotype of the HIF-3α KO ECs. Importantly, we found that the mRNA levels of HIF-2α and Ets-1 were significantly increased by HIF-3α ablation. Given that both factors are known to activate the VE-cadherin gene, the transcriptional repression of these factors by HIF-3α might be important for silencing the irrelevant expression of the VE-cadherin gene. Collectively, these data show novel and unique roles of HIF-3α for angiogenic gene regulation in pulmonary ECs.
authors.affiliation: Graduate School of Comprehensive Human Sciences, Laboratory of Regenerative Medicine and Stem Cell Biology, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, 305-8575, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yamashita
authors.forename: Kinuko
authors.initials: K
authors.lastname: Ohneda
authors.forename: Masumi
authors.initials: M
authors.lastname: Nagano
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kimura
authors.forename: Hideto
authors.initials: H
authors.lastname: Nakai
authors.forename: Lorenz
authors.initials: L
authors.lastname: Poellinger
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohneda
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D042783:Endothelial Cells / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000166:cytology*; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D042501:Angiogenic Proteins; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D015820:Cadherins; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000099152:Cadherin 5; C485502:HIF-2 protein, mouse; C444643:Hif3a protein, mouse