Hypoxia‐inducible factor‐3α promotes angiogenic activity of pulmonary endothelial cells by repressing the expression of the VE‐cadherin gene. (28th January 2015) - Kobayashi, Satomi
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.