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Hypoxia-inducible factor-3α promotes angiogenic activity of pulmonary endothelial cells by repressing the expression of the VE-cadherin gene.
- Source :
-
Genes to cells : devoted to molecular & cellular mechanisms [Genes Cells] 2015 Mar; Vol. 20 (3), pp. 224-41. Date of Electronic Publication: 2015 Jan 28. - Publication Year :
- 2015
-
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.<br /> (© 2015 The Authors Genes to Cells © 2015 by the Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.)
- Subjects :
- Angiogenic Proteins metabolism
Animals
Antigens, CD genetics
Apoptosis Regulatory Proteins
Cadherins genetics
Cell Hypoxia
Lung blood supply
Mice
Mice, Transgenic
Proto-Oncogene Proteins c-akt metabolism
Repressor Proteins
Vascular Endothelial Growth Factor A metabolism
Antigens, CD metabolism
Cadherins metabolism
Endothelial Cells metabolism
Lung cytology
Neovascularization, Physiologic
Transcription Factors genetics
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2443
- Volume :
- 20
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Genes to cells : devoted to molecular & cellular mechanisms
- Publication Type :
- Academic Journal
- Accession number :
- 25626335
- Full Text :
- https://doi.org/10.1111/gtc.12215