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Research Papers

Blood Pressure, Artery Size, and Artery Compliance Parallel Bone Size and Strength in Mice With Differing Ece1 Expression

[+] Author and Article Information
Zhijie Wang

Department of Biomedical Engineering,
University of Wisconsin,
2146 ECB, 1550 Engineering Drive,
Madison, WI 53706

Jasmin Kristianto

Geriatrics Research, Education, and Clinical Center,
William S. Middleton Veterans Hospital,
2500 Overlook Terrace,
Madison, WI 53705;
Division of Endocrinology,
Department of Medicine,
University of Wisconsin,
4148 MFCB (5148), 1685 Highland Avenue,
Madison, WI 53705;
Endocrine and Reproductive Physiology Program,
University of Wisconsin,
1465 MSC, 1300 University Avenue,
Madison, WI 53706

Chen Yen Ooi, Naomi C. Chesler

Department of Biomedical Engineering,
University of Wisconsin,
2146 ECB, 1550 Engineering Drive,
Madison, WI 53706

Gurpreet Sandhu

Geriatrics Research, Education, and Clinical Center,
William S. Middleton Veterans Hospital,
2500 Overlook Terrace,
Madison, WI 53705;
Division of Endocrinology,
Department of Medicine,
University of Wisconsin,
4148 MFCB (5148), 1685 Highland Avenue,
Madison, WI 53705

Robert D. Blank

Geriatrics Research, Education, and Clinical Center,
William S. Middleton Veterans Hospital,
2500 Overlook Terrace,
Madison, WI 53705;
Division of Endocrinology,
Department of Medicine,
University of Wisconsin,
4148 MFCB (5148), 1685 Highland Avenue,
Madison, WI 53705;
Endocrine and Reproductive Physiology Program,
University of Wisconsin,
1465 MSC, 1300 University Avenue,
Madison, WI 53706
e-mail: rdb@medicine.wisc.edu

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1Present address: Bioengineering Office, Department of Engineering, University of Cambridge, Trumpington Street, Cambridge, CB2 1PZ, UK.

2Present address: Faculty of Medicine, St. Martinus University, Brionplein 1, Otrobanda, P.O. Box 2050, Curaçao.

3Corresponding author.

Contributed by the Bioengineering Division of ASME for publication in the JOURNAL OF BIOMECHANICAL ENGINEERING. Manuscript received June 26, 2012; final manuscript received December 21, 2012; accepted manuscript posted April 8, 2013; published online May 9, 2013. Assoc. Editor: Hai-Chao Han.

J Biomech Eng 135(6), 061003 (May 09, 2013) (9 pages) Paper No: BIO-12-1246; doi: 10.1115/1.4024161 History: Received June 26, 2012; Revised December 21, 2012; Accepted April 08, 2013

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.

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References

Figures

Grahic Jump Location
Fig. 1

Ambulatory BP and heart size. The difference in (a) systolic (p = 0.002), (b) diastolic (p < 0.001) BP, and (c) normalized heart mass (p < 0.01) between HcB-8 and HcB-23 is significant. N = 8 for HcB-8 and 10 for HcB-23. * p < 0.05.

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Fig. 2

Carotid artery mechanical properties. (a) Stretch (λ) as a function of transmural pressure. (b) Compliance (c) as a function of transmural pressure. (c) Circumferential stress versus Green’s strain (σ–ε) obtained from 90 to 120 mm Hg. * p < 0.05. N = 10 for HcB-8 and N = 8 for HcB-23.

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Fig. 3

Expression levels of Ece1 and Nos3 in heart. Top, Ece1 mRNA (p < 0.001), Ece1 protein (p = 0.04). Bottom. Nos3 mRNA (p = 0.04), Nos3 protein (p = 0.008). * p < 0.05. N = 4/strain for all comparisons.

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Fig. 4

Expression levels of Ece1 and Nos3 in femoral artery. Relative Ece1 (p = 0.001, N = 5/strain) and Nos3 (p = 0.01, N = 5/strain) protein levels are higher in HcB-23 mice. * p < 0.05

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Fig. 5

Immunohistochemistry of hearts and carotid arteries. Heart (a)–(d) and carotid artery (e)–(h) stained as indicated. Ece1 (a), (b), (g), (h), Nos3 (c), (d), (i), (j), and PECAM1 (e), (f). HcB-8 (a), (c), (e), (g), (i), HcB-23 (b), (d), (f), (h), (j). Scale bars are 1 mm for heart sections and 50 μm for carotid artery sections.

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Fig. 6

Schematic of ET-1 signaling in HcB-8 and HcB-23 arteries. HcB-8 arteries (left) have low Ece1 expression. Big ET-1 is cleaved to active ET-1 primarily by tissue proteases and signaling SMC preferentially. A is the predominant receptor type in these cells, with its activation favoring SMC contraction and development of narrow, stiff vessels. HcB-23 arteries (right) have high Ece1 expression. Big ET-1 is cleaved to active ET-1 primarily by Ece1, signaling EC preferentially. B is the predominant receptor type in these cells, with its activation favoring NO production and development of wide, compliant vessels. A = A type ET-1 receptor. B = B type ET-1 receptor. EC = endothelial cell. SMC = smooth muscle cells. Sizes of symbols and arrows represent abundance of proteins and activity of pathways, respectively.

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