Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Angiogenesis
Published in: Angiogenesis 3/2016

01-07-2016 | Review Paper

ETS transcription factors in embryonic vascular development

Authors: Michael P. Craig, Saulius Sumanas

Published in: Angiogenesis | Issue 3/2016

Login to get access

Abstract

At least thirteen ETS-domain transcription factors are expressed during embryonic hematopoietic or vascular development and potentially function in the formation and maintenance of the embryonic vasculature or blood lineages. This review summarizes our current understanding of the specific roles played by ETS factors in vasculogenesis and angiogenesis and the implications of functional redundancies between them.
Literature
1.
Nunn MF, Seeburg PH, Moscovici C et al (1983) Tripartite structure of the avian erythroblastosis virus E26 transforming gene. Nature 306:391–395PubMedCrossRef
2.
Lelievre E, Lionneton F, Soncin F (2001) Role of the ETS transcription factors in the control of endothelial-specific gene expression and in angiogenesis. Bull Cancer 88:137–142PubMed
3.
Verger A, Buisine E, Carrere S et al (2001) Identification of amino acid residues in the ETS transcription factor Erg that mediate Erg-Jun/Fos-DNA ternary complex formation. J Biol Chem 276:17181–17189PubMedCrossRef
4.
De Val S, Chi NC, Meadows SM et al (2008) Combinatorial regulation of endothelial gene expression by ets and forkhead transcription factors. Cell 135:1053–1064PubMedPubMedCentralCrossRef
5.
Hollenhorst PC, Jones DA, Graves BJ (2004) Expression profiles frame the promoter specificity dilemma of the ETS family of transcription factors. Nucl Acids Res 32:5693–5702PubMedPubMedCentralCrossRef
6.
Wei G, Srinivasan R, Cantemir-Stone CZ et al (2009) Ets1 and Ets2 are required for endothelial cell survival during embryonic angiogenesis. Blood 114:1123–1130PubMedPubMedCentralCrossRef
7.
Liu F, Patient R (2008) Genome-wide analysis of the zebrafish ETS family identifies three genes required for hemangioblast differentiation or angiogenesis. Circ Res 103:1147–1154PubMedCrossRef
8.
Garrett-Sinha LA, Dahl R, Rao S et al (2001) PU.1 exhibits partial functional redundancy with Spi-B, but not with Ets-1 or Elf-1. Blood 97:2908–2912PubMedCrossRef
9.
Abedin MJ, Nguyen A, Jiang N et al (2014) Fli1 acts downstream of Etv2 to govern cell survival and vascular homeostasis via positive autoregulation. Circ Res 114:1690–1699PubMedPubMedCentralCrossRef
10.
Craig MP, Grajevskaja V, Liao HK et al (2015) Etv2 and fli1b function together as key regulators of vasculogenesis and angiogenesis. Arterioscler Thromb Vasc Biol 35:865–876PubMedPubMedCentralCrossRef
11.
Liu F, Li D, Yu YY et al (2015) Induction of hematopoietic and endothelial cell program orchestrated by ETS transcription factor ER71/ETV2. EMBO Rep 16:654–669PubMedPubMedCentralCrossRef
12.
Brown TA, McKnight SL (1992) Specificities of protein-protein and protein-DNA interaction of GABP alpha and two newly defined ets-related proteins. Genes Dev 6:2502–2512PubMedCrossRef
13.
Sumanas S, Jorniak T, Lin S (2005) Identification of novel vascular endothelial-specific genes by the microarray analysis of the zebrafish cloche mutants. Blood 106:534–541PubMedPubMedCentralCrossRef
14.
Hayashi M, Pluchinotta M, Momiyama A et al (2012) Endothelialization and altered hematopoiesis by persistent Etv2 expression in mice. Exp Hematol 40(738–750):e11PubMed
15.
Koyano-Nakagawa N, Kweon J, Iacovino M et al (2012) Etv2 is expressed in the yolk sac hematopoietic and endothelial progenitors and regulates Lmo2 gene expression. Stem Cells 30:1611–1623PubMedPubMedCentralCrossRef
16.
Lee D, Park C, Lee H et al (2008) ER71 acts downstream of BMP, Notch, and Wnt signaling in blood and vessel progenitor specification. Cell Stem Cell 2:497–507PubMedPubMedCentralCrossRef
17.
Ferdous A, Caprioli A, Iacovino M et al (2009) Nk2–5 transactivates the Ets-related protein 71 gene and specifies an endothelial/endocardial fate in the developing embryo. Proc Natl Acad Sci USA 106:814–819PubMedPubMedCentralCrossRef
18.
Sumanas S, Lin S (2006) Ets1-related protein is a key regulator of vasculogenesis in zebrafish. PLoS Biol 4:e10PubMedCrossRef
19.
Glenn NO, Schumacher JA, Kim HJ et al (2014) Distinct regulation of the anterior and posterior myeloperoxidase expression by Etv2 and Gata1 during primitive Granulopoiesis in zebrafish. Dev Biol 393:149–159PubMedPubMedCentralCrossRef
20.
Sumanas S, Gomez G, Zhao Y et al (2008) Interplay among Etsrp/ER71, Scl, and Alk8 signaling controls endothelial and myeloid cell formation. Blood 111:4500–4510PubMedPubMedCentralCrossRef
21.
Salanga MC, Meadows SM, Myers CT et al (2010) ETS family protein ETV2 is required for initiation of the endothelial lineage but not the hematopoietic lineage in the Xenopus embryo. Dev Dyn 239:1178–1187PubMedPubMedCentralCrossRef
22.
Moore JC, Sheppard-Tindell S, Shestopalov IA et al (2013) Post-transcriptional mechanisms contribute to Etv2 repression during vascular development. Dev Biol 384:128–140PubMedPubMedCentralCrossRef
23.
Park C, Lee TJ, Bhang SH et al (2016) Injury-mediated vascular regeneration requires endothelial ER71/ETV2. Arterioscler Thromb Vasc Biol 36:86–96PubMedCrossRef
24.
Pham VN, Lawson ND, Mugford JW et al (2007) Combinatorial function of ETS transcription factors in the developing vasculature. Dev Biol 303:772–783PubMedCrossRef
25.
Robinson AS, Materna SC, Barnes RM et al (2014) An arterial-specific enhancer of the human endothelin converting enzyme 1 (ECE1) gene is synergistically activated by Sox17, FoxC2, and Etv2. Dev Biol 395:379–389PubMedPubMedCentralCrossRef
26.
Palencia-Desai S, Kohli V, Kang J et al (2011) Vascular endothelial and endocardial progenitors differentiate as cardiomyocytes in the absence of Etsrp/Etv2 function. Development 138:4721–4732PubMedPubMedCentralCrossRef
27.
28.
Lee D, Kim T, Lim DS (2011) The Er71 is an important regulator of hematopoietic stem cells in adult mice. Stem Cells 29:539–548PubMedCrossRef
29.
Veldman MB, Zhao C, Gomez GA et al (2013) Transdifferentiation of fast skeletal muscle into functional endothelium in vivo by transcription factor Etv2. PLoS Biol 11:e1001590PubMedPubMedCentralCrossRef
30.
Ishitobi H, Wakamatsu A, Liu F et al (2011) Molecular basis for Flk1 expression in hemato-cardiovascular progenitors in the mouse. Development 138:5357–5368PubMedPubMedCentralCrossRef
31.
Veldman MB, Lin S (2012) Etsrp/Etv2 is directly regulated by Foxc1a/b in the zebrafish angioblast. Circ Res 110:220–229PubMedCrossRef
32.
Schupp MO, Waas M, Chun CZ et al (2014) Transcriptional inhibition of etv2 expression is essential for embryonic cardiac development. Dev Biol 393:71–83PubMedPubMedCentralCrossRef
33.
34.
35.
Wareing S, Mazan A, Pearson S et al (2012) The Flk1-Cre-mediated deletion of ETV2 defines its narrow temporal requirement during embryonic hematopoietic development. Stem Cells 30:1521–1531PubMedCrossRef
36.
Kohli V, Schumacher JA, Desai SP et al (2013) Arterial and venous progenitors of the major axial vessels originate at distinct locations. Dev Cell 25:196–206PubMedPubMedCentralCrossRef
37.
Thompson MA, Ransom DG, Pratt SJ et al (1998) The cloche and spadetail genes differentially affect hematopoiesis and vasculogenesis. Dev Biol 197:248–269PubMedCrossRef
38.
Shi X, Zirbes KM, Rasmussen TL et al (2015) The transcription factor Mesp1 interacts with cAMP-responsive element binding protein 1 (Creb1) and coactivates Ets variant 2 (Etv2) gene expression. J Biol Chem 290:9614–9625PubMedPubMedCentralCrossRef
39.
Zhang L, Lemarchandel V, Romeo PH et al (1993) The Fli-1 proto-oncogene, involved in erythroleukemia and Ewing’s sarcoma, encodes a transcriptional activator with DNA-binding specificities distinct from other Ets family members. Oncogene 8:1621–1630PubMed
40.
Stoll G, Surdez D, Tirode F et al (2013) Systems biology of Ewing sarcoma: a network model of EWS-FLI1 effect on proliferation and apoptosis. Nucleic Acids Res 41:8853–8871PubMedPubMedCentralCrossRef
41.
Spyropoulos DD, Pharr PN, Lavenburg KR et al (2000) Hemorrhage, impaired hematopoiesis, and lethality in mouse embryos carrying a targeted disruption of the Fli1 transcription factor. Mol Cell Biol 20:5643–5652PubMedPubMedCentralCrossRef
42.
Liu F, Walmsley M, Rodaway A et al (2008) Fli1 acts at the top of the transcriptional network driving blood and endothelial development. Curr Biol 18:1234–1240PubMedCrossRef
43.
Ren X, Gomez GA, Zhang B et al (2010) Scl isoforms act downstream of etsrp to specify angioblasts and definitive hematopoietic stem cells. Blood 115:5338–5346PubMedPubMedCentralCrossRef
44.
Wong KS, Proulx K, Rost MS et al (2009) Identification of vasculature-specific genes by microarray analysis of etsrp/etv2 overexpressing zebrafish embryos. Dev Dyn 238:1836–1850PubMedCrossRef
45.
Law SH, Sargent TD (2013) Maternal pak4 expression is required for primitive myelopoiesis in zebrafish. Mech Dev 130:181–194PubMedCrossRef
46.
Kruse EA, Loughran SJ, Baldwin TM et al (2009) Dual requirement for the ETS transcription factors Fli-1 and Erg in hematopoietic stem cells and the megakaryocyte lineage. Proc Natl Acad Sci USA 106:13814–13819PubMedPubMedCentralCrossRef
47.
Loughran SJ, Kruse EA, Hacking DF et al (2008) The transcription factor Erg is essential for definitive hematopoiesis and the function of adult hematopoietic stem cells. Nat Immunol 9:810–819PubMedCrossRef
48.
Giovannini M, Biegel JA, Serra M et al (1994) EWS-erg and EWS-Fli1 fusion transcripts in Ewing’s sarcoma and primitive neuroectodermal tumors with variant translocations. J Clin Invest 94:489–496PubMedPubMedCentralCrossRef
49.
Tomlins SA, Palanisamy N, Brenner JC et al (2013) Usefulness of a monoclonal ERG/FLI1 antibody for immunohistochemical discrimination of Ewing family tumors. Am J Clin Pathol 139:771–779PubMedPubMedCentralCrossRef
50.
Martens JH (2011) Acute myeloid leukemia: a central role for the ETS factor ERG. Int J Biochem Cell Biol 43:1413–1416PubMedCrossRef
51.
Baltzinger M, Mager-Heckel AM, Remy P (1999) Xl erg: expression pattern and overexpression during development plead for a role in endothelial cell differentiation. Dev Dyn 216:420–433PubMedCrossRef
52.
53.
Abzug MJ, Nachman SA, Muresan P et al (2013) Safety and immunogenicity of 2009 pH1N1 vaccination in HIV-infected pregnant women. Clin Infect Dis 56:1488–1497PubMedPubMedCentralCrossRef
54.
Carrere S, Verger A, Flourens A et al (1998) Erg proteins, transcription factors of the Ets family, form homo, heterodimers and ternary complexes via two distinct domains. Oncogene 16:3261–3268PubMedCrossRef
55.
56.
Birdsey GM, Shah AV, Dufton N et al (2015) The endothelial transcription factor ERG promotes vascular stability and growth through Wnt/beta-catenin signaling. Dev Cell 32:82–96PubMedPubMedCentralCrossRef
57.
58.
59.
Asano Y, Stawski L, Hant F et al (2010) Endothelial Fli1 deficiency impairs vascular homeostasis: a role in scleroderma vasculopathy. Am J Pathol 176:1983–1998PubMedPubMedCentralCrossRef
60.
61.
Ellett F, Kile BT, Lieschke GJ (2009) The role of the ETS factor erg in zebrafish vasculogenesis. Mech Dev 126:220–229PubMedCrossRef
62.
63.
Muthusamy N, Barton K, Leiden JM (1995) Defective activation and survival of T cells lacking the Ets-1 transcription factor. Nature 377:639–642PubMedCrossRef
64.
Bories JC, Willerford DM, Grevin D et al (1995) Increased T-cell apoptosis and terminal B-cell differentiation induced by inactivation of the Ets-1 proto-oncogene. Nature 377:635–638PubMedCrossRef
65.
Tanaka K, Oda N, Iwasaka C et al (1998) Induction of Ets-1 in endothelial cells during reendothelialization after denuding injury. J Cell Physiol 176:235–244PubMedCrossRef
66.
Iwasaka C, Tanaka K, Abe M et al (1996) Ets-1 regulates angiogenesis by inducing the expression of urokinase-type plasminogen activator and matrix metalloproteinase-1 and the migration of vascular endothelial cells. J Cell Physiol 169:522–531PubMedCrossRef
67.
Sato Y, Abe M, Tanaka K et al (2000) Signal transduction and transcriptional regulation of angiogenesis. Adv Exp Med Biol 476:109–115PubMedCrossRef
68.
Chen Z, Fisher RJ, Riggs CW et al (1997) Inhibition of vascular endothelial growth factor-induced endothelial cell migration by ETS1 antisense oligonucleotides. Cancer Res 57:2013–2019PubMed
69.
Watanabe D, Takagi H, Suzuma K et al (2004) Transcription factor Ets-1 mediates ischemia- and vascular endothelial growth factor-dependent retinal neovascularization. Am J Pathol 164:1827–1835PubMedPubMedCentralCrossRef
70.
Elvert G, Kappel A, Heidenreich R et al (2003) Cooperative interaction of hypoxia-inducible factor-2alpha (HIF-2alpha) and Ets-1 in the transcriptional activation of vascular endothelial growth factor receptor-2 (Flk-1). J Biol Chem 278:7520–7530PubMedCrossRef
71.
Dutta D, Ray S, Vivian JL et al (2008) Activation of the VEGFR1 chromatin domain: an angiogenic signal-ETS1/HIF-2alpha regulatory axis. J Biol Chem 283:25404–25413PubMedPubMedCentralCrossRef
72.
Nor JE, Christensen J, Mooney DJ et al (1999) Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. Am J Pathol 154:375–384PubMedPubMedCentralCrossRef
73.
Distel M, Wullimann MF, Koster RW (2009) Optimized Gal4 genetics for permanent gene expression mapping in zebrafish. Proc Natl Acad Sci U S A 106:13365–13370PubMedPubMedCentralCrossRef
74.
Rahim S, Uren A (2013) Emergence of ETS transcription factors as diagnostic tools and therapeutic targets in prostate cancer. Am J Transl Res 5:254–268PubMedPubMedCentral
75.
Paulo P, Ribeiro FR, Santos J et al (2012) Molecular subtyping of primary prostate cancer reveals specific and shared target genes of different ETS rearrangements. Neoplasia 14:600–611PubMedPubMedCentralCrossRef
76.
Nakano T, Abe M, Tanaka K et al (2000) Angiogenesis inhibition by transdominant mutant Ets-1. J Cell Physiol 184:255–262PubMedCrossRef
77.
Oda N, Abe M, Sato Y (1999) ETS-1 converts endothelial cells to the angiogenic phenotype by inducing the expression of matrix metalloproteinases and integrin beta3. J Cell Physiol 178:121–132PubMedCrossRef
78.
Lelievre E, Mattot V, Huber P et al (2000) ETS1 lowers capillary endothelial cell density at confluence and induces the expression of VE-cadherin. Oncogene 19:2438–2446PubMedCrossRef
79.
Lincoln DW 2nd, Phillips PG, Bove K (2003) Estrogen-induced Ets-1 promotes capillary formation in an in vitro tumor angiogenesis model. Breast Cancer Res Treat 78:167–178PubMedCrossRef
80.
Pourtier-Manzanedo A, Vercamer C, Van Belle E et al (2003) Expression of an Ets-1 dominant-negative mutant perturbs normal and tumor angiogenesis in a mouse ear model. Oncogene 22:1795–1806PubMedCrossRef
81.
Aperlo C, Pognonec P, Stanley ER et al (1996) Constitutive c-ets2 expression in M1D + myeloblast leukemic cells induces their differentiation to macrophages. Mol Cell Biol 16:6851–6858PubMedPubMedCentralCrossRef
82.
Polydorou C, Georgiades P (2013) Ets2-dependent trophoblast signalling is required for gastrulation progression after primitive streak initiation. Nat Commun 4:1658PubMedCrossRef
83.
84.
Kappel A, Schlaeger TM, Flamme I et al (2000) Role of SCL/Tal-1, GATA, and ets transcription factor binding sites for the regulation of flk-1 expression during murine vascular development. Blood 96:3078–3085PubMed
85.
86.
Wang X, Huang W, Liu G et al (2014) Cardiomyocytes mediate anti-angiogenesis in type 2 diabetic rats through the exosomal transfer of miR-320 into endothelial cells. J Mol Cell Cardiol 74:139–150PubMedPubMedCentralCrossRef
87.
Yoshimatsu Y, Yamazaki T, Mihira H et al (2011) Ets family members induce lymphangiogenesis through physical and functional interaction with Prox1. J Cell Sci 124:2753–2762PubMedCrossRef
88.
Wernert N, Okuducu AF, Pepper MS (2003) Ets 1 is expressed in capillary blood vessels but not in lymphatics. J Pathol 200:561–567PubMedCrossRef
89.
Thompson CB, Wang CY, Ho IC et al (1992) cis-acting sequences required for inducible interleukin-2 enhancer function bind a novel Ets-related protein, Elf-1. Mol Cell Biol 12:1043–1053PubMedPubMedCentralCrossRef
90.
Wang CY, Bassuk AG, Boise LH et al (1994) Activation of the granulocyte-macrophage colony-stimulating factor promoter in T cells requires cooperative binding of Elf-1 and AP-1 transcription factors. Mol Cell Biol 14:1153–1159PubMedPubMedCentralCrossRef
91.
Serdobova I, Pla M, Reichenbach P et al (1997) Elf-1 contributes to the function of the complex interleukin (IL)-2-responsive enhancer in the mouse IL-2 receptor alpha gene. J Exp Med 185:1211–1221PubMedPubMedCentralCrossRef
92.
Dube A, Thai S, Gaspar J et al (2001) Elf-1 is a transcriptional regulator of the Tie2 gene during vascular development. Circ Res 88:237–244PubMedCrossRef
93.
Sato TN, Tozawa Y, Deutsch U et al (1995) Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376:70–74PubMedCrossRef
94.
Karantzoulis-Fegaras F, Antoniou H, Lai SL et al (1999) Characterization of the human endothelial nitric-oxide synthase promoter. J Biol Chem 274:3076–3093PubMedCrossRef
95.
Hegen A, Koidl S, Weindel K et al (2004) Expression of angiopoietin-2 in endothelial cells is controlled by positive and negative regulatory promoter elements. Arterioscler Thromb Vasc Biol 24:1803–1809PubMedCrossRef
96.
Oettgen P, Akbarali Y, Boltax J et al (1996) Characterization of NERF, a novel transcription factor related to the Ets factor ELF-1. Mol Cell Biol 16:5091–5106PubMedPubMedCentralCrossRef
97.
Wang LC, Kuo F, Fujiwara Y et al (1997) Yolk sac angiogenic defect and intra-embryonic apoptosis in mice lacking the Ets-related factor TEL. EMBO J 16:4374–4383PubMedPubMedCentralCrossRef
98.
Gaspar J, Thai S, Voland C et al (2002) Opposing functions of the Ets factors NERF and ELF-1 during chicken blood vessel development. Arterioscler Thromb Vasc Biol 22:1106–1112PubMedCrossRef
99.
Lopez RG, Carron C, Oury C et al (1999) TEL is a sequence-specific transcriptional repressor. J Biol Chem 274:30132–30138PubMedCrossRef
100.
De Braekeleer E, Douet-Guilbert N, Morel F et al (2012) ETV6 fusion genes in hematological malignancies: a review. Leuk Res 36:945–961PubMedCrossRef
101.
Hock H, Meade E, Medeiros S et al (2004) Tel/Etv6 is an essential and selective regulator of adult hematopoietic stem cell survival. Genes Dev 18:2336–2341PubMedPubMedCentralCrossRef
102.
Roukens MG, Alloul-Ramdhani M, Baan B et al (2010) Control of endothelial sprouting by a Tel-CtBP complex. Nat Cell Biol 12:933–942PubMedCrossRef
103.
104.
Ciau-Uitz A, Pinheiro P, Gupta R et al (2010) Tel1/ETV6 specifies blood stem cells through the agency of VEGF signaling. Dev Cell 18:569–578PubMedCrossRef
Metadata
Title
ETS transcription factors in embryonic vascular development
Authors
Michael P. Craig
Saulius Sumanas
Publication date
01-07-2016
Publisher
Springer Netherlands
Published in
Angiogenesis / Issue 3/2016
Print ISSN: 0969-6970
Electronic ISSN: 1573-7209
DOI
https://doi.org/10.1007/s10456-016-9511-z

Other articles of this Issue 3/2016

Angiogenesis 3/2016 Go to the issue

Original Paper

mTORC2 mediates CXCL12-induced angiogenesis

Erratum

Erratum to: In situ validation of VEGFR-2 and α v ß 3 integrin as targets for breast lesion characterization

Review Paper

Plants and their active compounds: natural molecules to target angiogenesis

Original Paper

Association of endothelial proliferation with the magnitude of weight loss during calorie restriction

Original Paper

Circulating angiopoietin-2 levels in children and adolescents with type 1 diabetes mellitus: relation to carotid and aortic intima-media thickness

Original Paper

Pigment epithelium-derived factor (PEDF): a novel trophoblast-derived factor limiting feto-placental angiogenesis in late pregnancy

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits