Defective Connective Tissue Remodeling in Smad3 Mice Leads to Accelerated Aneurysmal Growth Through Disturbed Downstream TGF-β Signaling.
Aneurysm-osteoarthritis syndrome characterized by unpredictable aortic aneurysm formation, is caused by SMAD3 mutations. SMAD3 is part of the SMAD2/3/4 transcription factor, essential for TGF-β-activated transcription. Although TGF-β-related gene mutations result in aneurysms, the underlying mechanism is unknown. Here, we examined aneurysm formation and progression in Smad3-/-animals. Smad3-/-animals developed aortic aneurysms rapidly, resulting in premature death. Aortic wall immunohistochemistry showed no increase in extracellular matrix and collagen accumulation, nor loss of vascular smooth muscle cells (VSMCs) but instead revealed medial elastin disruption and adventitial inflammation. Remarkably, matrix metalloproteases (MMPs) were not activated in VSMCs, but rather specifically in inflammatory areas. Although Smad3-/-aortas showed increased nuclear pSmad2 and pErk, indicating TGF-β receptor activation, downstream TGF-β-activated target genes were not upregulated. Increased pSmad2 and pErk staining in pre-aneurysmal Smad3-/-aortas implied that aortic damage and TGF-β receptor-activated signaling precede aortic inflammation. Finally, impaired downstream TGF-β activated transcription resulted in increased Smad3-/-VSMC proliferation. Smad3 deficiency leads to imbalanced activation of downstream genes, no activation of MMPs in VSMCs, and immune responses resulting in rapid aortic wall dilatation and rupture. Our findings uncover new possibilities for treatment of SMAD3 patients; instead of targeting TGF-β signaling, immune suppression may be more beneficial.
Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Molecular Genetics, Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
I
I
van der Pluijm
Department of Molecular Genetics, Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, The Netherlands.
N
N
van Vliet
Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
J H
JH
von der Thusen
Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
J L
JL
Robertus
Department of Molecular Genetics, Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, The Netherlands.
Y
Y
Ridwan
Department of Molecular Genetics, Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
P M
PM
van Heijningen
Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Molecular Genetics, Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Pharmacology, Erasmus University Medical Center, Rotterdam, The Netherlands.
B S
BS
van Thiel
Department of Molecular Genetics, Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, The Netherlands.
M
M
Vermeij
Department of Anesthesiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
S E
SE
Hoeks
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
R M G B
RMGB
Buijs-Offerman
Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.
H J M
HJM
Verhagen
Department of Molecular Genetics, Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Radiation Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.
R
R
Kanaar
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
A M
AM
Bertoli-Avella
Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Molecular Genetics, Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Radiation Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands. Electronic address: j.essers@erasmusmc.nl.
J
J
Essers
D000783:Aneurysm / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D000818:Animals; D001014:Aortic Aneurysm / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D049109:Cell Proliferation; D003238:Connective Tissue / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D004452:Echocardiography; D004549:Elastin / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D057054:Molecular Imaging; D009026:Mortality; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D055114:X-Ray Microtomography
D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D004549:Elastin; D048049:Extracellular Signal-Regulated MAP Kinases; D020782:Matrix Metalloproteinases
Aneurysm; Echocardiography; Mouse model; TGF-β signaling pathway; Vascular biology
Int J Cardiol. 2013 May 10;165(2):314-21
21937134
EMBO J. 1998 Jun 1;17(11):3091-100
9606191
Ned Tijdschr Geneeskd. 2013;157(21):A5588
23693005
Genes Dev. 2002 Aug 1;16(15):1867-71
12154118
Circ Cardiovasc Imaging. 2010 Sep;3(5):567-77
20592247
Circulation. 1998 Nov 10;98(19 Suppl):II331-7; discussion II337-8
9852923
J Am Coll Cardiol. 2015 Apr 7;65(13):1324-36
25835445
PLoS One. 2014 May 07;9(5):e96387
24804794
J Med Genet. 2012 Jan;49(1):47-57
22167769
Genes Dev. 2005 Dec 1;19(23):2783-810
16322555
Arterioscler Thromb Vasc Biol. 2011 Apr;31(4):750-7
21252070
Spine (Phila Pa 1976). 2009 Jun 1;34(13):1363-9
19478656
Nat Genet. 2005 Mar;37(3):275-81
15731757
J Clin Invest. 2013 May;123(5):2317-31
23585475
J Bone Miner Res. 2006 Jan;21(1):4-16
16355269
Nat Rev Mol Cell Biol. 2012 Oct;13(10):616-30
22992590
J Clin Invest. 2002 Sep;110(5):625-32
12208863
J Hypertens. 2016 Apr;34(4):654-65
26828783
Nature. 1996 Sep 12;383(6596):168-72
8774881
Sci Rep. 2015 Nov 26;5:16872
26607280
Ann Thorac Surg. 2013 Jan;95(1):332-5
23272854
Nat Genet. 2012 Jul 08;44(8):916-21
22772371
Nat Genet. 1994 Dec;8(4):345-51
7894484
Circ Res. 2011 Sep 2;109(6):680-6
21778426
Circ Res. 2007 Aug 31;101(5):512-22
17641224
Nat Genet. 2012 Jul 27;44(8):838-9
22836090
Nat Genet. 2012 Jul 08;44(8):922-7
22772368
Nat Genet. 2007 Dec;39(12):1488-93
17994018
Clin Genet. 2013 Apr;83(4):337-44
22803640
J Am Coll Cardiol. 2012 Jul 31;60(5):397-403
22633655
Circ Res. 2007 Mar 16;100(5):738-46
17293478
Nat Genet. 2003 Mar;33(3):407-11
12598898
Nat Genet. 2006 Mar;38(3):343-9
16444274
J Clin Invest. 2004 Dec;114(11):1586-92
15546004
PLoS One. 2011;6(8):e23411
21858106
Methods Mol Biol. 2001;177:163-78
11530605
Eur J Hum Genet. 2010 Aug;18(8):895-901
20389311
Case Rep Genet. 2014;2014:591516
24711937
Nat Genet. 2004 Aug;36(8):855-60
15235604
Nat Med. 2007 Feb;13(2):204-10
17237794
Nature. 2011 May 19;473(7347):308-16
21593863
Circulation. 2003 Jan 21;107(2):333-8
12538437
Mol Cell Biol. 2006 Mar;26(5):1700-9
16478991
Semin Thorac Cardiovasc Surg. 2011 Summer;23(2):124-5
22041041
Am J Med Genet A. 2013 Aug;161A(8):2040-6
23824657
Circ Res. 2013 Jul 19;113(3):327-40
23868829
Oncogene. 2014 Jan 2;33(1):97-107
23208491
Ann Thorac Surg. 2006 Oct;82(4):1400-5
16996941
Am J Med Genet A. 2013 May;161A(5):1028-35
23554019
Science. 2006 Apr 7;312(5770):117-21
16601194
Circ Res. 2010 Feb 19;106(3):583-92
20019329
Nat Genet. 2011 Feb;43(2):121-6
21217753