title: Transcriptional and functional adaptations of human endothelial cells to physiological chronic low oxygen.
abstract: Endothelial cells chronically reside in low-O2 environments in vivo (2%-13% O2), which are believed to be critical for cell homeostasis. To elucidate the roles of this physiological chronic normoxia in human endothelial cells, we examined transcriptomes of human umbilical vein endothelial cells (HUVECs), proliferation and migration of HUVECs in response to fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor A (VEGFA), and underlying signaling mechanisms under physiological chronic normoxia. Immediately after isolation, HUVECs were cultured steadily under standard cell culture normoxia (SCN; 21% O2) or physiological chronic normoxia (PCN; 3% O2) up to 25 days. We found that PCN up-regulated 41 genes and down-regulated 21 genes, 90% of which differed from those previously reported from HUVECs cultured under SCN and exposed to acute low O2. Gene ontology analysis indicated that PCN-regulated genes were highly related to cell proliferation and migration, consistent with the results from benchtop assays that showed that PCN significantly enhanced FGF2- and VEGFA-stimulated cell proliferation and migration. Interestingly, preexposing the PCN cells to 21% O2 up to 5 days did not completely diminish PCN-enhanced cell proliferation and migration. These PCN-enhanced cell proliferations and migrations were mediated via augmented activation of MEK1/MEK2/ERK1/ERK2 and/or PI3K/AKT1. Importantly, these PCN-enhanced cellular responses were associated with an increase in activation of VEGFR2 but not FGFR1, without altering their expression. Thus, PCN programs endothelial cells to undergo dramatic changes in transcriptomes and sensitizes cellular proliferative and migratory responses to FGF2 and VEGFA. These PCN cells may offer a unique endothelial model, more closely mimicking the in vivo states.
authors.affiliation: Department of Obstetrics and Gynecology, University of Wisconsin, Madison, Wisconsin.
authors.forename: Yi-Zhou
authors.initials: YZ
authors.lastname: Jiang
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Cai-Feng
authors.initials: CF
authors.lastname: Dai
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Christina
authors.initials: C
authors.lastname: Kendziorski
authors.forename: Dong-Bao
authors.initials: DB
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: angiogenesis; growth factors; physiological chronic low oxygen; protein kinases; transcriptome
references.citation: Int J Mol Med. 2006 Apr;17(4):559-66
references.pmid: 16525710
references.citation: Placenta. 2009 Dec;30(12):1045-51
references.pmid: 19892399
references.citation: Am J Physiol. 1995 May;268(5 Pt 1):L789-800
references.pmid: 7539223
references.citation: Nat Rev Cancer. 2002 Jul;2(7):489-501
references.pmid: 12094235
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4547-52
references.pmid: 17360561
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15809-14
references.pmid: 9861052
references.citation: Science. 2002 May 31;296(5573):1655-7
references.pmid: 12040186
references.citation: Proteomics. 2004 Jun;4(6):1737-60
references.pmid: 15174142
references.citation: Mol Endocrinol. 2009 Sep;23(9):1428-44
references.pmid: 19477952
references.citation: J Clin Endocrinol Metab. 2004 May;89(5):2484-90
references.pmid: 15126581
references.citation: Am J Respir Cell Mol Biol. 2000 Nov;23(5):593-601
references.pmid: 11062137
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3756-9
references.pmid: 15738407
references.citation: Biol Reprod. 2008 Jan;78(1):143-50
references.pmid: 17901071
references.citation: Histochem Cell Biol. 2011 May;135(5):475-85
references.pmid: 21465248
references.citation: Endocrinology. 1999 Mar;140(3):1399-407
references.pmid: 10067868
references.citation: FASEB J. 2002 Jun;16(8):771-80
references.pmid: 12039858
references.citation: Blood. 2005 Feb 15;105(4):1383-95
references.pmid: 15471951
references.citation: Biol Reprod. 2000 Aug;63(2):559-69
references.pmid: 10906065
references.citation: Nucleic Acids Res. 2002 May 1;30(9):e36
references.pmid: 11972351
references.citation: Nat Med. 2003 Jun;9(6):677-84
references.pmid: 12778166
references.citation: Cardiovasc Res. 2011 Jan 1;89(1):157-65
references.pmid: 20675298
references.citation: Front Biosci. 2007 May 01;12:2967-77
references.pmid: 17485273
references.citation: Obstet Gynecol. 1992 Aug;80(2):283-5
references.pmid: 1635745
references.citation: FASEB J. 2006 Jul;20(9):1513-5
references.pmid: 16754745
references.citation: Placenta. 1996 Jan;17(1):49-55
references.pmid: 8710813
references.citation: Cell. 2012 Feb 3;148(3):399-408
references.pmid: 22304911
references.citation: Cell. 2010 May 28;141(5):872-83
references.pmid: 20471072
references.citation: Mol Biosyst. 2009 Dec;5(12):1512-26
references.pmid: 20023718
references.citation: Placenta. 2003 Feb-Mar;24(2-3):191-8
references.pmid: 12566246
references.citation: Biol Reprod. 2008 Oct;79(4):704-10
references.pmid: 18509162
references.citation: Am J Physiol. 1988 Sep;255(3 Pt 2):H554-62
references.pmid: 3414822
references.citation: Biotechnol Lett. 2004 Mar;26(6):509-15
references.pmid: 15127793
references.citation: Methods Enzymol. 2006;411:134-93
references.pmid: 16939790
references.citation: Nat Med. 2003 Jun;9(6):669-76
references.pmid: 12778165
references.citation: Hypertension. 2010 Apr;55(4):1005-11
references.pmid: 20212268
references.citation: Nat Rev Cancer. 2010 Feb;10(2):116-29
references.pmid: 20094046