Distinct roles of HIF1A in endothelial adaptations to physiological and ambient oxygen

•HIF1A overexpression enhanced endothelial proliferation and/or migration in 21% O2.•HIF1A knockdown failed to affect endothelial proliferation and migration in 3% O2.•HIF1A critically regulates human endothelial function in 21% O2, but not in 3% O2. Fetoplacental endothelial cells reside under phys...

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Veröffentlicht in:Molecular and cellular endocrinology 2014-06, Vol.391 (1-2), p.60-67
Hauptverfasser: Jiang, Yi-Zhou, Li, Yan, Wang, Kai, Dai, Cai-Feng, Huang, Shi-An, Chen, Dong-Bao, Zheng, Jing
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Sprache:eng
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Zusammenfassung:•HIF1A overexpression enhanced endothelial proliferation and/or migration in 21% O2.•HIF1A knockdown failed to affect endothelial proliferation and migration in 3% O2.•HIF1A critically regulates human endothelial function in 21% O2, but not in 3% O2. Fetoplacental endothelial cells reside under physiological normoxic conditions (∼2–8% O2) in vivo. Under such conditions, cells are believed to sense O2 changes primarily via hypoxia inducible factor 1 α (HIF1A). However, little is known regarding the role of HIF1A in fetoplacental endothelial function under physiological normoxia. We recently reported that physiological chronic normoxia (PCN; 20–25day, 3% O2) enhanced FGF2- and VEGFA-stimulated proliferation and migration of human umbilical vein endothelial cells (HUVECs) via the MEK/ERK1/2 and PI3K/AKT1 pathways compared to standard cell culture normoxia (SCN; ambient O2: ∼21% O2). Here, we investigated the action of HIF1A in regulating these cellular responses in HUVECs. HIF1A adenovirus infection in SCN-cells increased HIF1A protein expression, enhanced FGF2- and VEGFA-stimulated cell proliferation by 2.4 and 2.0-fold respectively, and promoted VEGFA-stimulated cell migration by 1.4-fold. HIF1A adenovirus infection in SCN-cells did not affect either basal or FGF2- and VEGFA-induced ERK1/2 activation, but it decreased basal AKT1 phosphorylation. Interestingly, HIF1A knockdown in PCN-cells via specific HIF1A siRNA transfection did not alter FGF2- and VEGFA-stimulated cell proliferation and migration, or ERK1/2 activation; however, it inhibited FGF2-induced AKT1 activation by ∼50%. These data indicate that HIF1A differentially regulates cell proliferation and migration, and ERK1/2 and AKT1 activation in PCN- and SCN-HUVECs. These data also suggest that HIF1A critically regulates cell proliferation and migration in SCN-, but not in PCN-HUVECs.
ISSN:0303-7207
1872-8057
DOI:10.1016/j.mce.2014.04.008