The recombinant congenic mouse strains HcB-8 and HcB-23 differ in femoral shape, size, and strength, with HcB-8 femora being more gracile, more cylindrical, weaker, and having higher Young's modulus. In previous work, we mapped a robust, pleiotropic quantitative trait locus for these bone traits. Ece1, encoding endothelin converting enzyme 1, is a positional candidate gene for this locus, and was less expressed in HcB-8 bone. We hypothesized that the same genetic factors would impose analogous developmental trajectories on arteries to those in bones. Cardiovascular hemodynamics and biomechanics of carotids were measured in adult HcB-8 and HcB-23 mice. Biological differences in heart and arteries were examined at mRNA and protein levels. As in bone, Ece1 expression was higher in HcB-23 heart and arteries (p < 0.05), and its expression was correlated with that of the endothelin B type receptor target Nos3, encoding endothelial nitric oxide synthase. HcB-8 mice had higher ambulatory blood pressure (p < 0.005) than HcB-23 mice. Ex vivo, at identical pressures, HcB-8 carotid arteries had smaller diameters and lower compliance (p < 0.05), but the same elastic modulus compared to HcB-23 carotid arteries. HcB-8 hearts were heavier than HcB-23 hearts (p < 0.01). HcB-8 has both small, stiff bones and small, stiff arteries, lower expression of Ece1 and Nos3, associated in each case with less favorable function. These findings suggest that endothelin signaling could serve as a nexus for the convergence of skeletal and vascular modeling, providing a potential mechanism for the epidemiologic association between skeletal fragility and atherosclerosis.

References

References
1.
Frost
,
H. M.
,
2001
, “
From Wolff's Law to the Utah Paradigm: Insights About Bone Physiology and Its Clinical Applications
,”
Anat. Rec.
,
262
, pp.
398
419
.10.1002/ar.1049
2.
Bonewald
,
L. F.
,
2006
, “
Mechanosensation and Transduction in Osteocytes
,”
Bonekey Osteovis.
,
3
, pp.
7
15
.10.1138/20060233
3.
Humphrey
,
J. D.
,
2008
, “
Mechanisms of Arterial Remodeling in Hypertension: Coupled Roles of Wall Shear and Intramural Stress
,”
Hypertension
,
52
, pp.
195
200
.10.1161/HYPERTENSIONAHA.107.103440
4.
Fox
,
S. W.
,
Chambers
,
T. J.
, and
Chow
,
J. W.
,
1996
, “
Nitric Oxide is an Early Mediator of the Increase in Bone Formation by Mechanical Stimulation
,”
Am. J. Physiol.
,
270
, pp.
E955
E960
.
5.
Balligand
,
J. L.
,
Feron
,
O.
, and
Dessy
C.
,
2009
, “
eNOS Activation by Physical Forces: From Short-Term Regulation of Contraction to Chronic Remodeling of Cardiovascular Tissues
,”
Physiol. Rev.
,
89
, pp.
481
534
.10.1152/physrev.00042.2007
6.
Helfrich
,
M. H.
,
Evans
,
D. E.
,
Grabowski
,
P. S.
,
Pollock
,
J. S.
,
Ohshima
,
H.
, and
Ralston
,
S. H.
,
1997
, “
Expression of Nitric Oxide Synthase Isoforms in Bone and Bone Cell Cultures
,”
J. Bone Miner. Res.
,
12
, pp.
1108
1115
.10.1359/jbmr.1997.12.7.1108
7.
Klein-Nulend
,
J.
,
Helfrich
,
M. H.
,
Sterck
,
J. G.
,
MacPherson
,
H.
,
Joldersma
,
M.
,
Ralston
,
S. H.
,
Semeins
,
C. M.
, and
Burger
,
E. H.
,
1998
, “
Nitric Oxide Response to Shear Stress by Human Bone Cell Cultures is Endothelial Nitric Oxide Synthase Dependent
,”
Biochem. Biophys. Res. Commun.
,
250
, pp.
108
114
.10.1006/bbrc.1998.9270
8.
MacPherson
,
H.
,
Noble
,
B. S.
, and
Ralston
,
S. H.
,
1999
, “
Expression and Functional Role of Nitric Oxide Synthase Isoforms in Human Osteoblast-Like Cells
,”
Bone
,
24
, pp.
179
185
.10.1016/S8756-3282(98)00173-2
9.
Tanko
,
L. B.
,
Christiansen
,
C.
,
Cox
,
D. A.
,
Geiger
,
M. J.
,
McNabb
,
M. A.
, and
Cummings
,
S. R.
,
2005
, “
Relationship Between Osteoporosis and Cardiovascular Disease in Postmenopausal Women
,”
J. Bone Miner. Res.
,
20
, pp.
1912
1920
.10.1359/JBMR.050711
10.
Ness
,
J.
, and
Aronow
,
W. S.
,
2006
, “
Comparison of Prevalence of Atherosclerotic Vascular Disease in Postmenopausal Women With Osteoporosis or Osteopenia Versus Without Osteoporosis or Osteopenia
,”
Am. J. Cardiol.
,
97
, pp.
1427
1428
.10.1016/j.amjcard.2005.12.033
11.
Sennerby
,
U.
,
Melhus
,
H.
,
Gedeborg
,
R.
,
Byberg
,
L.
,
Garmo
,
H.
,
Ahlbom
,
A.
,
Pedersen
,
N. L.
, and
Michaëlsson
,
K.
,
2009
, “
Cardiovascular Diseases and Risk of Hip Fracture
,”
JAMA
,
302
, pp.
1666
1673
.10.1001/jama.2009.1463
12.
Bagger
,
Y. Z.
,
Rasmussen
,
H. B.
,
Alexandersen
,
P.
,
Werge
,
T.
,
Christiansen
,
C.
, and
Tankó
,
L. B.
,
2007
, “
Links Between Cardiovascular Disease and Osteoporosis in Postmenopausal Women: Serum Lipids or Atherosclerosis Per Se?
,”
Osteoporos. Int.
,
18
, pp.
505
512
.10.1007/s00198-006-0255-2
13.
Sattler
,
A. M.
,
Schoppet
,
M.
,
Schaefer
,
J. R.
, and
Hofbauer
,
L. C.
,
2004
, “
Novel Aspects on RANK Ligand and Osteoprotegerin in Osteoporosis and Vascular Disease
,”
Calcif. Tissue Int.
74
, pp.
103
106
.
10.1007/s00223-003-0011-y
14.
Groot
,
P. C.
,
Moen
,
C. J.
,
Dietrich
,
W.
,
Stoye
,
J. P.
,
Lander
,
E. S.
, and
Demant
,
P.
,
1992
, “
The Recombinant Congenic Strains for Analysis of Multigenic Traits: Genetic Composition
,”
FASEB J.
,
6
, pp.
2826
2835
.
15.
Saless
,
N.
,
Litscher
,
S. J.
,
Lopez Franco
,
G. E.
,
Houlihan
,
M. J.
,
Sudhakaran
,
S.
,
Raheem
K. A.
,
O'Neil
,
T. K.
,
Vanderby
,
R.
,
Demant
,
P.
, and
Blank
,
R. D.
,
2009
, “
Quantitative Trait Loci for Biomechanical Performance and Femoral Geometry in an Intercross of Recombinant Congenic Mice: Restriction of the Bmd7 Candidate Interval
,”
FASEB J.
,
23
, pp.
2142
2154
.10.1096/fj.08-118679
16.
Saless
,
N.
,
Lopez Franco
,
G. E.
,
Litscher
,
S.
,
Kattappuram
,
R. S.
,
Houlihan
,
M. J.
,
Vanderby
,
R.
,
Demant
,
P.
, and
Blank
,
R. D.
,
2010
, “
Linkage Mapping of Femoral Material Properties in a Reciprocal Intercross of HcB-8 and HcB-23 Recombinant Mouse Strains
,”
Bone
,
46
, pp.
1251
1259
.10.1016/j.bone.2010.01.375
17.
Saless
,
N.
,
Litscher
,
S. J.
,
Houlihan
,
M. J.
,
Han
, I
. K.
,
Wilson
,
D.
,
Demant
,
P.
, and
Blank
,
R. D.
,
2011
, “
Comprehensive Skeletal Phenotyping and Linkage Mapping in an Intercross of Recombinant Congenic Mouse Strains HcB-8 and HcB-23
,”
Cells Tissues Organs
,
194
, pp.
244
248
.10.1159/000324774
18.
Saless
,
N.
,
Litscher
,
S. J.
,
Vanderby
,
R.
,
Demant
,
P.
, and
Blank
,
R. D.
,
2011
, “
Linkage Mapping of Principal Components for Femoral Biomechanical Performance in a Reciprocal HCB-8 x HCB-23 Intercross
,”
Bone
,
48
, pp.
647
653
.10.1016/j.bone.2010.10.165
19.
Xu
,
D.
,
Emoto
,
N.
,
Giaid
,
A.
,
Slaughter
,
C.
,
Kaw
,
S.
,
de Wit
,
D.
, and
Yanagisawa
,
M.
,
1994
, “
ECE-1: A Membrane-Bound Metalloprotease that Catalyzes the Proteolytic Activation of Big Endothelin-1
,”
Cell
,
78
, pp.
473
485
.10.1016/0092-8674(94)90425-1
20.
Gray
,
G. A.
, and
Webb
,
D. J.
,
1996
, “
The Endothelin System and its Potential as a Therapeutic Target in Cardiovascular Disease
,”
Pharmacol. Ther.
,
72
, pp.
109
148
.10.1016/S0163-7258(96)00101-5
21.
Marsen
,
T. A.
,
Egink
,
G.
,
Suckau
,
G.
, and
Baldamus
,
C. A.
,
1999
, “
Tyrosine-Kinase-Dependent Regulation of the Nitric Oxide Synthase Gene by Endothelin-1 in Human Endothelial Cells
,”
Pflugers Arch.
,
438
, pp.
538
544
.10.1007/s004240051073
22.
Herrera
,
M.
, and
Garvin
,
J. L.
,
2004
, “
Endothelin Stimulates Endothelial Nitric Oxide Synthase Expression in the Thick Ascending Limb
,”
Am. J. Physiol. Renal Physiol.
,
287
, pp.
F231
F235
.10.1152/ajprenal.00413.2003
23.
Ooi
,
C. Y.
,
Wang
,
Z.
,
Tabima
,
D. M.
,
Eickhoff
,
J. C.
, and
Chesler
,
N. C.
,
2010
, “
The Role of Collagen in Extralobar Pulmonary Artery Stiffening in Response to Hypoxia-Induced Pulmonary Hypertension
,”
Am. J. Physiol. Heart Circ. Physiol.
,
299
, pp.
H1823
H1831
.10.1152/ajpheart.00493.2009
24.
Fung
,
Y. C.
, and
Liu
,
S. Q.
,
1991
, “
Changes of Zero-Stress State of Rat Pulmonary Arteries in Hypoxic Hypertension
,”
J. Appl. Physiol.
,
70
, pp.
2455
2470
.10.1063/1.349398
25.
Lemma
,
M.
,
Innorta
,
A.
,
Pettinari
,
M.
,
Mangini
,
A.
,
Gelpi
,
G.
,
Piccaluga
,
M.
,
Danna
,
P.
, and
Antona
,
C.
,
2006
, “
Flow Dynamics and Wall Shear Stress in the Left Internal Thoracic Artery: Composite Arterial Graft Versus Single Graft
,”
Eur. J. Cardiothorac. Surg.
,
29
, pp.
473
478
.10.1016/j.ejcts.2006.01.035
26.
Peterson
,
L. H.
,
Jensen
,
R. E.
, and
Parnell
,
J.
,
1960
, “
Mechanical Properties of Arteries In Vivo
,”
Circ. Res.
,
8
, pp.
622
639
.10.1161/01.RES.8.3.622
27.
Kobs
,
R. W.
,
Muvarak
,
N. E.
,
Eickhoff
,
J. C.
, and
Chesler
,
N. C.
,
2005
, “
Linked Mechanical and Biological Aspects of Remodeling in Mouse Pulmonary Arteries With Hypoxia-Induced Hypertension
,”
Am. J. Physiol. Heart Circ. Physiol.
,
288
, pp.
H1209
H1217
.10.1152/ajpheart.01129.2003
28.
Kobs
,
R. W.
, and
Chesler
,
N. C.
,
2006
, “
The Mechanobiology of Pulmonary Vascular Remodeling in the Congenital Absence of eNOS
,”
Biomech. Model. Mechanobiol.
,
5
, pp.
217
225
.10.1007/s10237-006-0018-1
29.
Zhao
,
J.
,
Day
,
J.
,
Yuan
,
Z. F.
,
Gregersen
,
H.
,
2002
, “
Regional Arterial Stress-Strain Distributions Referenced to the Zero-Stress State in the Rat
,”
Am. J. Physiol. Heart Circ. Physiol.
,
282
, pp.
H622
H629
.
30.
Edwards
,
C. A.
, and
O'Brien
,
W. D.
, Jr.
,
1980
, “
Modified Assay for Determination of Hydroxyproline in a Tissue Hydrolyzate
,”
Clin. Chim. Acta
,
104
, pp.
161
167
.10.1016/0009-8981(80)90192-8
31.
Barger
,
J. L.
,
Kayo
,
T.
,
Pugh
,
T. D.
,
Prolla
,
T. A.
, and
Weindruch
,
R.
,
2008
, “
Short-Term Consumption of a Resveratrol-Containing Nutraceutical Mixture Mimics Gene Expression of Long-Term Caloric Restriction in Mouse Heart
,”
Exp. Gerontol.
,
43
, pp.
859
866
.10.1016/j.exger.2008.06.013
32.
Turner
,
C. H.
, and
Burr
,
D. B.
,
1993
, “
Basic Biomechanical Measurements of Bone: A Tutorial
,”
Bone
,
14
, pp.
595
608
.10.1016/8756-3282(93)90081-K
33.
Lucitti
,
J. L.
,
Jones
,
E. A.
,
Huang
,
C.
,
Chen
,
J.
,
Fraser
,
S. E.
, and
Dickinson
,
M. E.
,
2007
, “
Vascular Remodeling of the Mouse Yolk Sac Requires Hemodynamic Force
,”
Development
,
134
, pp.
3317
3326
.10.1242/dev.02883
34.
Hall
,
C. E.
,
Hurtado
,
R.
,
Hewett
,
K. W.
,
Shulimovich
,
M.
,
Poma
,
C. P.
,
Reckova
,
M.
,
Justus
,
C.
,
Pennisi
,
D. J.
,
Tobita
,
K.
,
Sedmera
,
D.
,
Gourdie
,
R. G.
, and
Mikawa
,
T.
,
2004
, “
Hemodynamic-Dependent Patterning of Endothelin Converting Enzyme 1 Expression and Differentiation of Impulse-Conducting Purkinje Fibers in the Embryonic Heart
,”
Development
,
131
, pp.
581
592
.10.1242/dev.00947
35.
Sedmera
,
D.
,
Harris
,
B. S.
,
Grant
,
E.
,
Zhang
,
N.
,
Jourdan
,
J.
,
Kurkova
,
D.
, and
Gourdie
,
R. G.
,
2008
, “
Cardiac Expression Patterns of Endothelin-Converting Enzyme (ECE): Implications for Conduction System Development
,”
Dev. Dyn.
,
237
, pp.
1746
1753
.10.1002/dvdy.21572
36.
Takebayashi-Suzuki
,
K.
,
Yanagisawa
,
M.
,
Gourdie
,
R. G.
,
Kanzawa
,
N.
, and
Mikawa
,
T.
,
2000
, “
In Vivo Induction of Cardiac Purkinje Fiber Differentiation by Coexpression of Preproendothelin-1 and Endothelin Converting Enzyme-1
,”
Development
,
127
, pp.
3523
3532
.
37.
Tuttle
,
J. L.
,
Nachreiner
,
R. D.
,
Bhuller
,
A. S.
,
Condict
,
K. W.
,
Connors
,
B. A.
,
Herring
,
B. P.
,
Dalsing
,
M. C.
, and
Unthank
,
J. L.
,
2001
, “
Shear Level Influences Resistance Artery Remodeling: Wall Dimensions, Cell Density, and eNOS Expression
,”
Am. J. Physiol. Heart Circ. Physiol.
,
281
, pp.
H1380
H1389
.
38.
Korshunov
, V
. A.
, and
Berk
,
B. C.
,
2004
, “
Strain-Dependent Vascular Remodeling: The ‘Glagov Phenomenon’ is Genetically Determined
,”
Circulation
,
110
, pp.
220
226
.10.1161/01.CIR.0000134958.88379.2E
39.
Mawji
, I
. A.
, and
Marsden
,
P. A.
,
2003
, “
Perturbations in Paracrine Control of the Circulation: Role of the Endothelial-Derived Vasomediators, Endothelin-1 and Nitric Oxide
,”
Microsc. Res. Tech.
,
60
, pp.
46
58
.10.1002/jemt.10242
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