Loss of Estrogen-Related Receptor Alpha Facilitates Angiogenesis in Endothelial Cells.
Angiogenesis Inducing Agents
/ metabolism
Animals
Cell Adhesion
/ genetics
Cell Movement
/ genetics
Endothelial Cells
/ metabolism
Energy Metabolism
/ physiology
Gene Expression Regulation, Neoplastic
/ genetics
Human Umbilical Vein Endothelial Cells
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Neovascularization, Physiologic
/ physiology
Organelle Biogenesis
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
/ metabolism
Receptors, Estrogen
/ genetics
Signal Transduction
/ physiology
Transcription Factors
/ metabolism
Vascular Endothelial Growth Factor A
/ metabolism
ERRalpha Estrogen-Related Receptor
angiogenesis
endothelial cell
estrogen-related receptors
nuclear receptor
regulation of gene expression
Journal
Molecular and cellular biology
ISSN: 1098-5549
Titre abrégé: Mol Cell Biol
Pays: United States
ID NLM: 8109087
Informations de publication
Date de publication:
01 03 2019
01 03 2019
Historique:
received:
16
08
2018
accepted:
11
12
2018
pubmed:
4
1
2019
medline:
4
12
2019
entrez:
4
1
2019
Statut:
epublish
Résumé
Estrogen-related receptors (ERRs) have emerged as major metabolic regulators in various tissues. However, their expression and function in the vasculature remains unknown. Here, we report the transcriptional program and cellular function of ERRα in endothelial cells (ECs), a cell type with a multifaceted role in vasculature. Of the three ERR subtypes, ECs exclusively express ERRα. Gene expression profiling of ECs lacking ERRα revealed that ERRα predominantly acts as a transcriptional repressor, targeting genes linked with angiogenesis, cell migration, and cell adhesion. ERRα-deficient ECs exhibit decreased proliferation but increased migration and tube formation. ERRα depletion increased basal as well as vascular endothelial growth factor A (VEGFA)- and ANG1/2-stimulated angiogenic sprouting in endothelial spheroids. Moreover, retinal angiogenesis is enhanced in ERRα knockout mice compared to that in wild-type mice. Surprisingly, ERRα is dispensable for the regulation of its classic targets, such as metabolism, mitochondrial biogenesis, and cellular respiration in the ECs. ERRα is enriched at the promoters of angiogenic, migratory, and cell adhesion genes. Further, VEGFA increased ERRα recruitment to angiogenesis-associated genes and simultaneously decreased their expression. Despite increasing its gene occupancy, proangiogenic stimuli decrease ERRα expression in ECs. Our work shows that endothelial ERRα plays a repressive role in angiogenesis and potentially fine-tunes growth factor-mediated angiogenesis.
Identifiants
pubmed: 30602497
pii: MCB.00411-18
doi: 10.1128/MCB.00411-18
pmc: PMC6379583
pii:
doi:
Substances chimiques
Angiogenesis Inducing Agents
0
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
0
Receptors, Estrogen
0
Transcription Factors
0
Vascular Endothelial Growth Factor A
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL129191
Pays : United States
Informations de copyright
Copyright © 2019 American Society for Microbiology.
Références
Dev Cell. 2009 Feb;16(2):180-95
pubmed: 19217421
Arterioscler Thromb Vasc Biol. 2014 Jun;34(6):1231-9
pubmed: 24700124
Circulation. 2001 Jan 23;103(3):423-8
pubmed: 11157695
OMICS. 2012 May;16(5):284-7
pubmed: 22455463
Nat Genet. 2000 May;25(1):25-9
pubmed: 10802651
Cold Spring Harb Perspect Biol. 2013 Sep 01;5(9):
pubmed: 24003209
Nat Commun. 2016 Jul 20;7:12240
pubmed: 27436424
Genome Res. 2012 Sep;22(9):1798-812
pubmed: 22955990
Oncogene. 2007 Jun 14;26(28):4158-70
pubmed: 17173062
J Biol Chem. 2003 Sep 5;278(36):34598-604
pubmed: 12819200
Cell. 2011 Sep 16;146(6):873-87
pubmed: 21925313
J Steroid Biochem Mol Biol. 2009 Mar;114(1-2):106-12
pubmed: 19429439
Nucleic Acids Res. 2016 Jul 8;44(W1):W160-5
pubmed: 27079975
J Clin Invest. 2006 Jan;116(1):125-36
pubmed: 16374519
Acta Pharmacol Sin. 2015 Jan;36(1):51-61
pubmed: 25500872
PLoS One. 2016 May 09;11(5):e0154987
pubmed: 27159530
Cell Metab. 2011 Mar 2;13(3):283-93
pubmed: 21356518
Lab Invest. 1988 Sep;59(3):353-6
pubmed: 3411936
Cardiovasc Res. 1999 Jan;41(1):55-64
pubmed: 10325953
Biochim Biophys Acta. 2015 Sep;1852(9):1912-27
pubmed: 26115970
Cell. 1995 Dec 15;83(6):835-9
pubmed: 8521507
Microsc Res Tech. 2003 Jan 1;60(1):76-84
pubmed: 12500264
Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6472-7
pubmed: 15087503
J Burn Care Res. 2010 Jan-Feb;31(1):158-75
pubmed: 20061852
Genes Dev. 2007 Aug 1;21(15):1909-20
pubmed: 17671090
Am J Physiol Cell Physiol. 2002 May;282(5):C1181-90
pubmed: 11940533
Int J Dev Biol. 2011;55(4-5):353-63
pubmed: 21732275
Diabetes Res Clin Pract. 2003 Oct;62(1):1-8
pubmed: 14581151
Circ Res. 2013 May 10;112(10):1380-400
pubmed: 23661712
Genes Dev. 1999 Apr 15;13(8):1037-49
pubmed: 10215630
Curr Hypertens Rep. 2014 Jan;16(1):408
pubmed: 24343167
Pharmacol Rev. 2016 Jul;68(3):872-87
pubmed: 27363442
Nat Rev Immunol. 2007 Oct;7(10):803-15
pubmed: 17893694
Cell Metab. 2013 Nov 5;18(5):634-47
pubmed: 23973331
Mol Cell Biol. 2003 Nov;23(22):7947-56
pubmed: 14585956
Cell Rep. 2016 Feb 2;14(4):920-931
pubmed: 26804918
Arterioscler Thromb Vasc Biol. 2001 Jan;21(1):6-12
pubmed: 11145928
Nature. 2015 Apr 9;520(7546):192-197
pubmed: 25830893
J Vis Exp. 2013 Jul 09;(77):e50546
pubmed: 23892721
Cell Metab. 2007 May;5(5):345-56
pubmed: 17488637
Nature. 2012 Sep 6;489(7414):57-74
pubmed: 22955616
Nature. 1988 Jan 7;331(6151):91-4
pubmed: 3267207
Annu Rev Physiol. 2017 Feb 10;79:43-66
pubmed: 27992732
J Am Coll Cardiol. 1998 Jun;31(7):1555-60
pubmed: 9626834
J Mol Endocrinol. 2013 Nov 26;51(3):T115-40
pubmed: 24096517
Endocrinology. 2003 Jul;144(7):2785-90
pubmed: 12810531
Circ Res. 2012 Apr 13;110(8):1087-96
pubmed: 22415017
J Diabetes Res. 2016;2016:8492353
pubmed: 28053991
J Biol Chem. 1997 Dec 12;272(50):31693-9
pubmed: 9395511
PLoS One. 2015 Dec 02;10(12):e0143650
pubmed: 26630461
Cold Spring Harb Perspect Med. 2012 Sep 01;2(9):a006452
pubmed: 22951440
Endocr Rev. 2008 Oct;29(6):677-96
pubmed: 18664618
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1418-23
pubmed: 17229846
J Clin Invest. 1998 Jul 1;102(1):176-83
pubmed: 9649571
Cardiovasc Res. 2008 May 1;78(2):203-12
pubmed: 18079100
Genome Biol. 2008;9(9):R137
pubmed: 18798982
Clin Cancer Res. 2006 May 15;12(10):3003-9
pubmed: 16707595
Circ Res. 2007 Mar 30;100(6):782-94
pubmed: 17395884
Biochem Soc Trans. 2009 Dec;37(Pt 6):1233-6
pubmed: 19909253
Mol Cell. 2010 May 28;38(4):576-89
pubmed: 20513432
Mol Endocrinol. 2014 Dec;28(12):2060-71
pubmed: 25361393
J Biol Chem. 2010 Jul 16;285(29):22619-29
pubmed: 20418374
Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12378-83
pubmed: 14530391
J Cell Sci. 1999 Oct;112 ( Pt 19):3249-58
pubmed: 10504330
Eur Heart J. 2012 Apr;33(7):829-37, 837a-837d
pubmed: 21890489
Cell Metab. 2007 Jul;6(1):13-24
pubmed: 17618853
Arterioscler Thromb Vasc Biol. 2010 Aug;30(8):1535-41
pubmed: 20631354
J Biol Chem. 2002 Oct 25;277(43):40265-74
pubmed: 12181319
Biomed Res Int. 2014;2014:683025
pubmed: 24689049
Circ Res. 2013 Apr 26;112(9):1272-87
pubmed: 23620236
Nature. 1997 Apr 17;386(6626):671-4
pubmed: 9109485
Curr Med Chem. 2000 May;7(5):519-31
pubmed: 10702622
Inflamm Regen. 2017 Jan 18;37:2
pubmed: 29259701
Tissue Barriers. 2015 Apr 03;3(1-2):e978720
pubmed: 25838983
Annu Rev Pharmacol Toxicol. 2015;55:289-312
pubmed: 25251996
Endocr Rev. 1999 Oct;20(5):689-725
pubmed: 10529899
Cell Metab. 2018 Dec 4;28(6):881-894.e13
pubmed: 30146488
PLoS One. 2011;6(11):e27385
pubmed: 22110636
PLoS One. 2010 Dec 31;5(12):e14476
pubmed: 21217824
Cold Spring Harb Perspect Med. 2013 Jan 01;3(1):a006569
pubmed: 23085847
Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18348-53
pubmed: 22042850
Circulation. 1995 Feb 1;91(3):755-63
pubmed: 7530174
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2604-9
pubmed: 11226286
Mol Cell Endocrinol. 2018 Apr 15;465:82-91
pubmed: 29024781
Methods Mol Biol. 2016;1430:167-77
pubmed: 27172953
J Vis Exp. 2010 Dec 14;(46):
pubmed: 21178973
Mol Ther. 2018 Oct 3;26(10):2466-2475
pubmed: 30120059