1.
Golledge J, Norman PE. Atherosclerosis and abdominal aortic aneurysm:
cause, response, or common risk factors? Arterioscler Thromb Vasc Biol.
2010;30(6):1075-7. doi: 10.1161/ATVBAHA.110.206573. PubMed PMID: 20484703;
PubMed Central PMCID: PMC2874982.
2.
Daugherty A, Cassis LA. Mouse models of abdominal aortic aneurysms.
Arteriosclerosis, thrombosis, and vascular biology. 2004;24(3):429-34. doi:
10.1161/01.ATV.0000118013.72016.ea. PubMed PMID: 14739119.
3.
Patelis N, Moris D, Schizas D, Damaskos C, Perrea D, Bakoyiannis C, et al.
Animal models in the research of abdominal aortic aneurysms development.
Physiological research. 2017;66(6):899-915. PubMed PMID: 28937252.
4.
Ailawadi G, Eliason JL, Upchurch GR, Jr. Current concepts in the
pathogenesis of abdominal aortic aneurysm. J Vasc Surg. 2003;38(3):584-8. Epub
2003/08/30. doi: S0741521403003240 [pii]. PubMed PMID: 12947280.
5.
Longo GM, Xiong W, Greiner TC, Zhao Y, Fiotti N, Baxter BT. Matrix
metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest.
2002;110(5):625-32. Epub 2002/09/05. doi: 10.1172/JCI15334. PubMed PMID:
12208863.
6.
Annambhotla S, Bourgeois S, Wang X, Lin PH, Yao Q, Chen C. Recent
advances in molecular mechanisms of abdominal aortic aneurysm formation. World
journal of surgery. 2008;32(6):976-86. doi: 10.1007/s00268-007-9456-x. PubMed
PMID: 18259804; PubMed Central PMCID: PMC2927355.
7.
Golledge J, Muller J, Daugherty A, Norman P. Abdominal aortic aneurysm:
pathogenesis and implications for management. Arterioscler Thromb Vasc Biol.
2006;26(12):2605-13. doi: 10.1161/01.ATV.0000245819.32762.cb. PubMed PMID:
16973970.
8.
Baud'huin M, Duplomb L, Teletchea S, Lamoureux F, Ruiz-Velasco C,
Maillasson M, et al. Osteoprotegerin: multiple partners for multiple functions. Cytokine
Growth Factor Rev. 2013;24(5):401-9. doi: 10.1016/j.cytogfr.2013.06.001. PubMed
PMID: 23827649.
9.
Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, et al.
Osteoprotegerin: a novel secreted protein involved in the regulation of bone density.
Cell. 1997;89(2):309-19. PubMed PMID: 9108485.
18
10.
Tsuda E, Goto M, Mochizuki S, Yano K, Kobayashi F, Morinaga T, et al.
Isolation of a novel cytokine from human fibroblasts that specifically inhibits
osteoclastogenesis. Biochem Biophys Res Commun. 1997;234(1):137-42. Epub
1997/05/08. doi: S0006291X97966031 [pii]. PubMed PMID: 9168977.
11.
Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, et al.
osteoprotegerin-deficient mice develop early onset osteoporosis and arterial
calcification. Genes & development. 1998;12(9):1260-8. PubMed PMID: 9573043;
PubMed Central PMCID: PMC316769.
12.
Sattler AM, Schoppet M, Schaefer JR, Hofbauer LC. Novel aspects on RANK
ligand and osteoprotegerin in osteoporosis and vascular disease. Calcified tissue
international. 2004;74(1):103-6. doi: 10.1007/s00223-003-0011-y. PubMed PMID:
14523602.
13.
Zhang J, Fu M, Myles D, Zhu X, Du J, Cao X, et al. PDGF induces
osteoprotegerin expression in vascular smooth muscle cells by multiple signal
pathways. FEBS Lett. 2002;521(1-3):180-4. Epub 2002/06/18. doi:
S0014579302028727 [pii]. PubMed PMID: 12067713.
14.
Jono S, Otsuki S, Higashikuni Y, Shioi A, Mori K, Hara K, et al. Serum
osteoprotegerin levels and long-term prognosis in subjects with stable coronary artery
disease. J Thromb Haemost. 2010;8(6):1170-5. doi: 10.1111/j.1538-7836.2010.03833.x.
PubMed PMID: 20230427.
15.
Schoppet M, Sattler AM, Schaefer JR, Herzum M, Maisch B, Hofbauer LC.
Increased osteoprotegerin serum levels in men with coronary artery disease. The Journal
of clinical endocrinology and metabolism. 2003;88(3):1024-8. doi: 10.1210/jc.2002020775. PubMed PMID: 12629080.
16.
Moran CS, McCann M, Karan M, Norman P, Ketheesan N, Golledge J.
Association of osteoprotegerin with human abdominal aortic aneurysm progression.
Circulation. 2005;111(23):3119-25. Epub 2005/06/09. doi:
CIRCULATIONAHA.104.464727 [pii]
10.1161/CIRCULATIONAHA.104.464727. PubMed PMID: 15939823.
17.
Koole D, Hurks R, Schoneveld A, Vink A, Golledge J, Moran CS, et al.
Osteoprotegerin is associated with aneurysm diameter and proteolysis in abdominal
aortic aneurysm disease. Arterioscler Thromb Vasc Biol. 2012;32(6):1497-504. Epub
2012/04/21. doi: ATVBAHA.111.243592 [pii]
19
10.1161/ATVBAHA.111.243592. PubMed PMID: 22516062.
18.
Bumdelger B, Kokubo H, Kamata R, Fujii M, Yoshimura K, Aoki H, et al.
Osteoprotegerin Prevents Development of Abdominal Aortic Aneurysms. PloS one.
2016;11(1):e0147088. doi: 10.1371/journal.pone.0147088. PubMed PMID: 26783750.
19.
Moran CS, Jose RJ, Biros E, Golledge J. Osteoprotegerin Deficiency Limits
Angiotensin II-Induced Aortic Dilatation and Rupture in the Apolipoprotein EKnockout Mouse. Arteriosclerosis, thrombosis, and vascular biology.
2014;34(12):2609-16. doi: 10.1161/ATVBAHA.114.304587. PubMed PMID:
25301844; PubMed Central PMCID: PMC4239170.
20.
Vorkapic E, Kunath A, Wagsater D. Effects of osteoprotegerin/TNFRSF11B
in two models of abdominal aortic aneurysms. Molecular medicine reports.
2018;18(1):41-8. doi: 10.3892/mmr.2018.8936. PubMed PMID: 29749489; PubMed
Central PMCID: PMC6059691.
21.
Daugherty A, Manning MW, Cassis LA. Antagonism of AT2 receptors
augments angiotensin II-induced abdominal aortic aneurysms and atherosclerosis. Br J
Pharmacol. 2001;134(4):865-70. Epub 2001/10/19. doi: 10.1038/sj.bjp.0704331.
PubMed PMID: 11606327.
22.
Biernacka A, Dobaczewski M, Frangogiannis NG. TGF-beta signaling in
fibrosis. Growth Factors. 29(5):196-202. Epub 2011/07/12. doi:
10.3109/08977194.2011.595714. PubMed PMID: 21740331.
23.
Kavurma MM, Schoppet M, Bobryshev YV, Khachigian LM, Bennett MR.
TRAIL stimulates proliferation of vascular smooth muscle cells via activation of NFkappaB and induction of insulin-like growth factor-1 receptor. J Biol Chem.
2008;283(12):7754-62. Epub 2008/01/08. doi: M706927200 [pii]
10.1074/jbc.M706927200. PubMed PMID: 18178561.
24.
Wei W, Wang D, Shi J, Xiang Y, Zhang Y, Liu S, et al. Tumor necrosis factor
(TNF)-related apoptosis-inducing ligand (TRAIL) induces chemotactic migration of
monocytes via a death receptor 4-mediated RhoGTPase pathway. Mol Immunol.
47(15):2475-84. Epub 2010/07/20. doi: S0161-5890(10)00473-6 [pii]
10.1016/j.molimm.2010.06.004. PubMed PMID: 20638129.
25.
Leask A. Potential therapeutic targets for cardiac fibrosis: TGFbeta,
angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation. Circ Res.
2010;106(11):1675-80. doi: 10.1161/CIRCRESAHA.110.217737. PubMed PMID:
20
20538689.
26.
Malfait F. Vascular aspects of the Ehlers-Danlos Syndromes. Matrix biology :
journal of the International Society for Matrix Biology. 2018;71-72:380-95. doi:
10.1016/j.matbio.2018.04.013. PubMed PMID: 29709596.
27.
Dobrin PB, Mrkvicka R. Failure of elastin or collagen as possible critical
connective tissue alterations underlying aneurysmal dilatation. Cardiovasc Surg.
1994;2(4):484-8. Epub 1994/08/01. PubMed PMID: 7953454.
28.
Yurovsky VV. Tumor necrosis factor-related apoptosis-inducing ligand
enhances collagen production by human lung fibroblasts. Am J Respir Cell Mol Biol.
2003;28(2):225-31. Epub 2003/01/24. doi: 10.1165/rcmb.2002-0140OC. PubMed
PMID: 12540490.
29.
Trachet B, Aslanidou L, Piersigilli A, Fraga-Silva RA, Sordet-Dessimoz J,
Villanueva-Perez P, et al. Angiotensin II infusion into ApoE-/- mice: a model for aortic
dissection rather than abdominal aortic aneurysm? Cardiovascular research.
2017;113(10):1230-42. doi: 10.1093/cvr/cvx128. PubMed PMID: 28898997.
30.
Lederle FA. The natural history of abdominal aortic aneurysm. Acta Chir
Belg. 2009;109(1):7-12. Epub 2009/04/04. PubMed PMID: 19341189.
21
Figure legends
Figure 1. Opg deficiency tends to suppress AngII-induced aortic aneurysms
(A) Aortas of AngII-infused ApoE-/-Opg+/+ and ApoE-/-Opg-/- mice were categorized into three
groups based on diameter and the presence of visible hematoma (No Aneurysm, Aneurysm, and
Dissection groups). Scale bars indicate 1 mm. (B) External diameter of the SRA in AngII-infused
ApoE-/-Opg+/+ (gray, n=16) and ApoE-/-Opg-/- (white, n=16) mice. All measurements are shown as
box plots and each measurement is shown as a white circle (No Aneurysm), gray triangle
(Aneurysm), or black cross (Dissection). (C) The incidence (%) of aortic aneurysms is shown for
No Aneurysm (white), Aneurysm (gray), and Dissection (black) groups. Statistical significance:
p<0.05.
Figure 2. Opg deficiency tends to suppress AngII-induced aortic dilatation and promotes
adventitial thickening
(A) Representative cross sections of the aorta stained with HE, EVG, and AZAN. Areas selected
by boxes surrounded by a black dotted line are magnified below. Scale bars indicate 0.1 mm. (B)
Internal area of the suprarenal aorta (SRA) of ApoE-/-Opg+/+ (n=16) and ApoE-/-Opg-/- (n=16) mice.
Measurements for all samples are presented as box plots. Measurements for the three groups are
presented as bar graphs. n=4 and 8 for the No-aneurysm group, n=5 and 5 for the Aneurysm group,
and n=7 and 3 for the Dissection group in ApoE-/-Opg+/+ and ApoE-/-Opg-/- mice, respectively. (C)
Medial layer width of the SRA of AngII-infused mice in each group. N.S; not significant. (D)
Relative adventitial area of the SRA of AngII-infused mice in each group. Statistical significance:
p<0.05.
22
Figure 3. Collagen accumulation in aortas of ApoE-/-Opg-/- mice
(A) Representative immunofluorescence images of aortas of AngII-infused mice stained with an
anti-collagen I antibody. Boxed areas (with white dotted lines) are magnified below. Scale bars
indicate 100 μm. (B) Percent area of collagen I expression in aortas of ApoE-/-Opg+/+ (n=16) and
ApoE-/-Opg-/- (n=16) mice. Measurements for all samples are presented as box plots.
Measurements for the three groups are presented as bar graphs (n=4 and 8 for the No Aneurysm
group, n=5 and 5 for the Aneurysm group, and n=7 and 3 for the Dissection group in ApoE-/Opg+/+ and ApoE-/-Opg-/- mice, respectively). (C) Tgf-β1 mRNA expression in the SRA at days 0,
7, and 28 after initiation of AngII infusion in ApoE-/-Opg+/+ (n=4, 5, 5) and ApoE-/-Opg-/- (n=5, 5,
5) mice. Statistical significance: p<0.05.
Figure 4. Accumulation of myofibroblasts in adventitias of AngII-infused ApoE-/-Opg-/- mice.
(A) Representative double-immunofluorescence images of aortas after AngII infusion with antiSMA (green) and anti-vimentin (red) antibodies. Scale bars indicate 100 μm. Areas selected by
the white box (dotted line) are magnified below. Nuclei were stained with DAPI (blue). Scale bars
indicate 25 μm. Medial layer (m), Adventitial layer (a), hematoma (b). The two arrowheads show
borders of the medial layer. The white dotted line in the magnified panels indicates the border of
the medial and adventitial layers. (B) Percent area of SMA expression in adventitias of ApoE-/Opg+/+ (n=16) and ApoE-/-Opg-/- (n=16) mice. Measurements for all samples are presented as box
plots. Measurements for the three groups are presented as bar graphs. n=4 and 8 for the No
Aneurysm group, n=5 and 5 for the Aneurysm group, and n=7 and 3 for the Dissection group in
ApoE-/-Opg+/+ and ApoE-/-Opg-/- mice, respectively. Statistical significance: p<0.05.
23
Figure 5. Trail upregulation in aneurysm tissue of AngII-infused ApoE-/-Opg-/- mice.
(A) Representative immunofluorescence images of aortic tissue sections from AngII-infused mice
stained with anti-Trail (green) antibody. Scale bars indicate 100 μm. Areas selected by the white
box (dotted line) in the Aneurysm group are magnified below. (B) Magnified
immunofluorescence images of aortic tissue sections from the AngII-infused Aneurysm group
stained with anti-Trail (green; a, f), anti-SMA (green; b, g), anti-vimentin (red; c, h), anti-Ki67
(red; d, i), and anti-F4/80 (red; e, j) antibodies in ApoE-/-Opg+/+ and ApoE-/-Opg-/- mice. Nuclei
were stained with DAPI (blue; c-DAPI, h-DAPI). Scale bars indicate 25 μm. Medial layer (m),
adventitial layer (a). The two arrowheads show borders of the medial layer. The white dotted line
in the magnified panels indicates the border of the medial and adventitial layers. Small arrows in
panel j indicate large round-shaped macrophages infiltrating the adventitia. Statistical
significance: p<0.05. (C) Percent area of Trail expression in medial and adventitial layers of
ApoE-/-Opg+/+ (n=16) and ApoE-/-Opg-/- (n=16) mice. Measurements for all samples are presented
as box plots. Measurements for the three groups are presented as bar graphs. n=4 and 8 for the
No Aneurysm group, n=5 and 5 for the Aneurysm group, and n=7 and 3 for the Dissection group
in ApoE-/-Opg+/+ and ApoE-/-Opg-/- mice, respectively. Statistical significance: p<0.05.
24
Bumdelger et al.
Figure 1
Aneurysm
Dissection
ApoE-/Opg +/+
No-aneurysm
Aneurysm
Dissection
p=0.21
2.5
ApoE -/- Opg +/+
2.0
ApoE -/- Opg -/-
1.5
Dissection
Aneurysm
No-aneurysm
1.0
0.5
p=0.09
100
3.0
AngII
% of Incidence
External diameter of SRA(mm)
ApoE -/Opg -/-
No-aneurysm
80
Dissection
Aneurysm
No-aneurysm
60
40
20
ApoE -/Opg +/+
ApoE -/Opg -/-
No-aneurysm
Aneurysm
ApoE -/- Opg +/+
Bumdelger et al.
Figure 2
HE
EVG
AZAN
Dissection
No-aneurysm
Aneurysm
ApoE -/- Opg
-/-
Dissection
Internal area of
SRA(mm2 )
0.5
1.0
1.5
p=0.04
ApoE -/- ApoE -/Opg +/+ Opg -/-
p=0.07
p=0.01
ApoE -/- ApoE -/Opg +/+ Opg -/-
N.S.
N.S.
N.S.
ApoE -/Opg -/-
N.S.
N.S.
p=0.13
ApoE -/Opg +/+
0.5
0.4
0.3
0.2
0.1
1.0
0.8
0.6
0.4
0.2
Width of medial
layer(mm)
Relative area of
adventitia
No-aneurysm
Aneurysm
Dissection
No-aneurysm
Aneurysm
Dissection
All samples
No-aneurysm
Aneurysm
Dissection
Bumdelger et al.
Figure 3
ApoE -/- Opg +/+
Aneurysm
Dissection
No-aneurysm
Aneurysm
Dissection
Collagen I
No-aneurysm
ApoE -/- Opg -/-
N.S.
p<0.01
p<0.05
p<0.05
60
All samples
No-aneurysm
Aneurysm
Dissection
40
20
ApoE -/Opg +/+
ApoE -/Opg -/-
TGF-b1 expression in SRA
% of Collagen I expression
area in aorta
2.52.5
p=0.05
p=0.01
N.S.
N.S.
2.02
1.51.5
1.01
0.50.5
00 0
0d
7d
28d
AngII
ApoE -/+/+
Opg
0d
7d
28d
AngII
ApoE -/Opg -/-
Bumdelger et al.
Figure 4
ApoE -/- Opg -/-
ApoE -/- Opg +/+
Dissection
Aneurysm
No-aneurysm
Aneurysm
Dissection
Merged
Vimentin
SMA
No-aneurysm
DAPI
% of SMA expression area
in the adventitial layer of aorta
N.S.
p<0.01
N.S.
p<0.05
30
All samples
No-aneurysm
Aneurysm
Dissection
20
10
ApoE -/Opg +/+
ApoE -/Opg -/-
Bumdelger et al.
Figure 5
ApoE -/- Opg -/-
ApoE -/- Opg +/+
Aneurysm
Dissection
No-aneurysm
Aneurysm
Dissection
Trail
No-aneurysm
ApoE -/- Opg -/-
ApoE -/- Opg +/+
Aneurysm
Trail
SMA
Vimentin
Trail
SMA
Vimentin
F·
K·
% of TRAIL expression area
in aorta
Ki67
Aneurysm
F4/80
DAPI
Ki67
p<0.05
p<0.01
N.S.
p<0.01
30
All samples
No-aneurysm
Aneurysm
Dissection
20
10
ApoE -/Opg +/+
ApoE -/Opg -/-
F4/80
DAPI
...
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