| First Author | Kobayashi S | Year | 2015 |
| Journal | Genes Cells | Volume | 20 |
| Issue | 3 | Pages | 224-41 |
| PubMed ID | 25626335 | Mgi Jnum | J:230264 |
| Mgi Id | MGI:5755900 | Doi | 10.1111/gtc.12215 |
| Citation | Kobayashi S, et al. (2015) Hypoxia-inducible factor-3alpha promotes angiogenic activity of pulmonary endothelial cells by repressing the expression of the VE-cadherin gene. Genes Cells 20(3):224-41 |
| abstractText | The variants of the hypoxia-inducible factor-3alpha gene HIF-3alpha and NEPAS are known to repress the transcriptional activities driven by HIF-1alpha and HIF-2alpha. Although NEPAS has been shown to play an important role in vascular remodeling during lung development, little is known about the roles of HIF-3alpha in adult lung function. Here, we examined pulmonary endothelial cells (ECs) isolated from wild-type (WT) and HIF-3alpha functional knockout (KO) mice. The expression levels of angiogenic factors (Flk1, Ang2 and Tie2) were significantly greater in the HIF-3alpha KO ECs than those in the WT ECs irrespective of oxygen tension. However, the HIF-3alpha 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-3alpha KO ECs. Importantly, we found that the mRNA levels of HIF-2alpha and Ets-1 were significantly increased by HIF-3alpha ablation. Given that both factors are known to activate the VE-cadherin gene, the transcriptional repression of these factors by HIF-3alpha might be important for silencing the irrelevant expression of the VE-cadherin gene. Collectively, these data show novel and unique roles of HIF-3alpha for angiogenic gene regulation in pulmonary ECs. |
