title: Distinct roles of HIF1A in endothelial adaptations to physiological and ambient oxygen.
abstract: 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; 20-25 day, 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.
authors.affiliation: Department of Obstetrics and Gynecology, University of Wisconsin, Madison, WI 53715, United States.
authors.forename: Yi-Zhou
authors.initials: YZ
authors.lastname: Jiang
authors.affiliation: Department of Obstetrics and Gynecology, University of Wisconsin, Madison, WI 53715, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 200040, PR China.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, University of Wisconsin, Madison, WI 53715, United States.
authors.forename: Cai-Feng
authors.initials: CF
authors.lastname: Dai
authors.affiliation: Department of Cardiovascular Medicine, Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, Guangdong, PR China.
authors.forename: Shi-An
authors.initials: SA
authors.lastname: Huang
authors.affiliation: Department of Obstetrics and Gynecology, University of California, Irvine, CA 92697, United States; Department of Pathology, University of California, Irvine, CA 92697, United States.
authors.forename: Dong-Bao
authors.initials: DB
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, University of Wisconsin, Madison, WI 53715, United States; Department of Cardiovascular Medicine, Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, Guangdong, PR China. Electronic address: jzheng@wisc.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics*; D000256:Adenoviridae / Q000235:genetics; D015687:Cell Hypoxia; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000187:drug effects; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases; D010100:Oxygen
keywords: Endothelial cells; Growth factors; HIF1A; Hypoxia; Protein kinases