Endoglin plays distinct roles in vascular smooth muscle cell recruitment and regulation of arteriovenous identity during angiogenesis.
Blood vessel formation is a multi-step process. Endoglin is a TGFbeta coreceptor required for angiogenesis. Endoglin null embryos exhibit a loss of arteriovenous identity and defective vascular smooth muscle cell (vSMC) recruitment. Haploinsufficiency of endoglin results in Hereditary Hemorrhagic Telangiectasia (HHT), characterized by a loss of arteriovenous identity and aberrant vSMC incorporation in fragile vessels. We explored a cell-autonomous role for endoglin in endothelial and vSMCs during angiogenesis by conditionally activating endoglin expression in wild type or endoglin null embryos using either smooth muscle (SM22alphacre) or endothelial cell (Tie2cre) promoters to partially rescue vSMC recruitment to the dorsal aorta. Examination of endoglin null embryos revealed ectopic arterial expression of the venous-specific marker COUPTFII. Endoglin re-expression in endothelial cells restored normal COUPTFII expression. These results suggested that endoglin plays distinct and cell-autonomous roles in vSMC recruitment and arteriovenous specification via COUPTFII in angiogenesis that may contribute to HHT.
Mancini
Maria L
ML
Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine, USA.
Terzic
Aleksandra
A
Conley
Barbara A
BA
Oxburgh
Leif H
LH
Nicola
Teodora
T
Vary
Calvin P H
CP
D000818:Animals; D001158:Arteries / Q000254:growth & development / Q000378:metabolism; D051837:COUP Transcription Factor II / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000378:metabolism; D000071063:Endoglin; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009024:Morphogenesis / Q000502:physiology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics / Q000378:metabolism; D014680:Veins / Q000254:growth & development / Q000378:metabolism; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism
D051837:COUP Transcription Factor II; D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; C497587:Nr2f2 protein, mouse; C051615:transgelin; D014841:von Willebrand Factor; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse
Development. 2008 May;135(10):1823-32
18417617
J Biol Chem. 2003 Aug 15;278(33):30478-86
12777384
Nature. 2005 Dec 15;438(7070):937-45
16355211
Blood. 1999 Jun 15;93(12):4284-92
10361126
Genesis. 2000 Feb;26(2):118-20
10686603
Cytotherapy. 2006;8(3):215-27
16793731
Mol Cell Biol. 2001 Feb;21(4):1336-44
11158319
Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17132-7
15569937
Nat Rev Genet. 2002 Sep;3(9):674-82
12209142
Prog Retin Eye Res. 1999 Jul;18(4):511-27
10217481
Genesis. 2001 May;30(1):36-44
11353516
Cardiovasc Res. 2001 Feb 16;49(3):507-21
11166264
Curr Opin Cell Biol. 2001 Oct;13(5):563-8
11544024
J Clin Invest. 2007 Feb;117(2):353-63
17273555
Annu Rev Cell Dev Biol. 2005;21:659-93
16212511
Genesis. 2005 Nov;43(3):148-53
16267823
Genesis. 2007 Jun;45(6):391-5
17506087
Science. 1999 May 28;284(5419):1534-7
10348742
Trends Cardiovasc Med. 2000 Oct;10(7):279-85
11343967
Atherosclerosis. 2000 Dec;153(2):323-35
11164421
Nat Med. 2000 Apr;6(4):389-95
10742145
J Anat. 2003 Jan;202(1):105-12
12587925
Dev Biol. 2000 Jan 1;217(1):42-53
10625534
Hum Mol Genet. 2000 Mar 22;9(5):745-55
10749981
J Clin Invest. 1999 Nov;104(10):1343-51
10562296
BMC Med. 2006 Dec 26;4(1):38
17190588
Nat Genet. 1994 Dec;8(4):345-51
7894484
Dev Biol. 2001 Feb 15;230(2):230-42
11161575
Mol Cell Biol. 1999 Apr;19(4):2734-45
10082539
Nature. 2005 May 5;435(7038):98-104
15875024
J Cell Physiol. 2005 Aug;204(2):574-84
15702480
Nat Genet. 1996 Jun;13(2):189-95
8640225
Hypertension. 2002 Nov;40(5):713-20
12411467
Circulation. 1997 Dec 16;96(12):4333-42
9416901
EXS. 1997;79:419-28
9002230
Nat Med. 2003 Jun;9(6):661-8
12778164
Eur J Immunol. 1993 Sep;23(9):2340-5
8370410
Dev Dyn. 2007 Aug;236(8):2089-100
17654716
Arch Pediatr Adolesc Med. 2006 Jun;160(6):596-601
16754821
Nature. 2005 Dec 15;438(7070):932-6
16355210
Proc Natl Acad Sci U S A. 2001 May 8;98(10):5377-8
11344278
Proc Natl Acad Sci U S A. 2002 May 14;99(10):7142-7
11997476
Dev Biol. 1999 Aug 1;212(1):191-203
10419695
Nat Genet. 2000 Nov;26(3):328-31
11062473
Circ Res. 2009 Mar 13;104(5):576-88
19286613
Mol Cell Biol. 2000 Feb;20(3):957-70
10629053
Dev Biol. 2007 Aug 15;308(2):520-33
17628518
Circ Res. 2005 Sep 16;97(6):512-23
16166562
J Biol Chem. 2006 Sep 1;281(35):25110-23
16785228
Dev Biol. 2003 Sep 1;261(1):235-50
12941632
J Biol Chem. 2004 Jun 25;279(26):27440-9
15084601
Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2626-31
10716993
Pediatrics. 2002 Jan;109(1):E12
11773580
Nat Med. 2003 Jun;9(6):685-93
12778167
Cardiovasc Res. 2005 Feb 15;65(3):599-608
15664386