Abstract
The stiffness and structural integrity of the arterial wall depends primarily on the organization of the extracellular matrix and the cells that fashion and maintain this matrix. Fundamental to the latter is a delicate balance in the continuous production and removal of structural constituents and the mechanical state in which such turnover occurs. Perturbations in this balance due to genetic mutations, altered hemodynamics, or pathological processes result in diverse vascular phenotypes, many of which have yet to be well characterized biomechanically. In this paper, we emphasize the particular need to understand regional variations in the biaxial biomechanical properties of central arteries in health and disease and, in addition, the need for standardization in the associated biaxial testing and quantification. As an example of possible experimental methods, we summarize testing protocols that have evolved in our laboratory over the past 8 years. Moreover, we note advantages of a four fiber family stress–stretch relation for quantifying passive biaxial behaviors, the use of stored energy as a convenient scalar metric of the associated material stiffness, and the utility of appropriate linearizations of the nonlinear, anisotropic relations both for purposes of comparison across laboratories and to inform computational fluid-solid-interaction models. We conclude that, notwithstanding prior advances, there remain many opportunities to advance our understanding of arterial mechanics and mechanobiology, particularly via the diverse genetic, pharmacological, and surgical models that are, or soon will be, available in the mouse.
Similar content being viewed by others
References
Adji, A., M. F. O’Rourke, and M. Namasivayam. Arterial stiffness, its assessment, prognostic value, and implications for treatment. Am. J. Hypertens. 24:5–17, 2011.
Agianniotis, A., A. Rachev, and N. Stergiopulos. Active axial stress in mouse aorta. J. Biomech. 45:1924–1927, 2012.
Agianniotis, A., and N. Stergiopulos. Wall properties of the apolipoprotein E-deficient mouse aorta. Atherosclerosis 223:314–320, 2012.
Baek, S., R. L. Gleason, K. R. Rajagopal, and J. D. Humphrey. Theory of small on large: potential utility in computations of fluid–solid interactions in arteries. Comput. Methods Appl. Mech. Eng. 196:3070–3078, 2007.
Bersi, M. R., M. J. Collins, E. Wilson, and J. D. Humphrey. Disparate changes in the mechanical properties of murine carotid arteries and aorta in response to chronic infusion of angiotensin-II. Int. J. Adv. Eng. Sci. Appl. Math. 4:228–240, 2012.
Cardamone, L., A. Valentín, J. F. Eberth, and J. D. Humphrey. Modelling carotid artery adaptations to dynamic alterations in pressure and flow over the cardiac cycle. Math. Med. Biol. 27:343–371, 2010.
Carta, L., J. E. Wagenseil, R. H. Knutsen, B. Mariko, G. Faury, E. C. Davis, B. Starcher, R. P. Mecham, and F. Ramirez. Discrete contributions of elastic fiber components to arterial development and mechanical compliance. Arterioscler. Thromb. Vasc. Biol. 29:2083–2089, 2009.
Cheng, J. K., I. Stoilov, R. P. Mecham, and J. E. Wagenseil. A fiber-based constitutive model predicts changes in amount and organization of matrix proteins with development and disease in the mouse aorta. Biomech. Model. Mechanobiol., 2012 [Epub ahead of print].
Chung, A. W. Y., H. H. C. Yang, and C. van Breeman. Imbalanced synthesis of cyclooxygenase-derived thromboxane A2 and prostacyclin compromises vasomotor function of the thoracic aorta in Marfan syndrome. Brit. J. Pharmacol. 152:305–312, 2007.
Chung, A. W. Y., K. A. Yeung, G. G. S. Sandor, D. P. Judge, H. C. Dietz, and C. van Breemen. Loss of elastic fiber integrity and reduction of vascular smooth muscle contraction resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in the thoracic aortic aneurysm in Marfan syndrome. Circ. Res. 101:512–522, 2007.
Chuong, C. J., and Y. C. Fung. On residual stresses in arteries. J. Biomech. Eng. 108:189–192, 1986.
Collins, M. J., M. R. Bersi, E. Wilson, and J. D. Humphrey. Mechanical properties of suprarenal and infrarenal abdominal aorta: implications for mouse models of aneurysms. Med. Eng. Phys. 33:1262–1269, 2011.
Cox, R. H. Regional variation of series elasticity in canine arterial smooth muscle. Am. J. Physiol. Heart. Circ. Physiol. 234:H542–H551, 1978.
Cox, R. H. Comparison of arterial wall mechanics using ring and cylindrical segments. Am. J. Physiol. Heart Circ. Physiol. 244:H298–H303, 1983.
Dingemans, K. P., P. Teeling, J. H. Lagendijk, and A. E. Becker. Extracellular matrix of the human aortic media: an ultrastructural histochemical and immunohistochemical study of the adult aortic media. Anat. Rec. 258:1–14, 2000.
Dobrin, P. B. Biaxial anisotropy of dog carotid artery: estimation of circumferential elastic modulus. J. Biomech. 19:351–358, 1986.
Dye, W. W., R. L. Gleason, E. Wilson, and J. D. Humphrey. Altered biomechanical properties of carotid arteries in two mouse models of muscular dystrophy. J. Appl. Physiol. 103:664–672, 2007.
Eberth, J. F., L. Cardamone, and J. D. Humphrey. Evolving biaxial mechanical properties of mouse carotid arteries in hypertension. J. Biomech. 44:2532–2537, 2011.
Eberth, J. F., V. C. Gresham, A. K. Reddy, N. Popovic, E. Wilson, and J. D. Humphrey. Importance of pulsatility in hypertensive carotid artery growth and remodeling. J. Hyptertens. 27:2010–2021, 2009.
Eberth, J. F., N. Popovic, V. C. Gresham, E. Wilson, and J. D. Humphrey. Time course of carotid artery growth and remodeling in response to altered pulsatility. Am. J. Physiol. Heart. Circ. Physiol. 299:H1875–H1883, 2010.
Eberth, J. F., A. I. Taucer, E. Wilson, and J. D. Humphrey. Mechanics of carotid arteries in a mouse model of Marfan syndrome. Ann. Biomed. Eng. 37:1093–1104, 2009.
Ferruzzi, J., M. J. Collins, A. T. Yeh, and J. D. Humphrey. Mechanical assessment of elastin integrity in fibrillin-1-deficient carotid arteries: implications for Marfan syndrome. Cardiovasc. Res. 92:287–295, 2011.
Ferruzzi, J., D. A. Vorp, and J. D. Humphrey. On constitutive descriptors of the biaxial mechanical behaviour of human abdominal aorta and aneurysms. J. R. Soc. Interface 8:435–450, 2011.
Figueroa, C. A., S. Baek, C. A. Taylor, and J. D. Humphrey. A computational framework for fluid-solid-growth modeling in cardiovascular simulations. Comput. Methods Appl. Mech. Eng. 198:3583–3602, 2009.
Fleenor, B. S., K. D. Marshall, J. R. Durrant, L. A. Lesniewski, and D. R. Seals. Arterial stiffening with ageing is associated with transforming growth factor-β1-related changes in adventitial collagen: reversal by aerobic exercise. J. Physiol. 588:3971–3982, 2010.
Fung, Y. C. Elasticity of soft tissues in simple elongation. Am. J. Physiol. 213:1532–1544, 1967.
Fung, Y. C. Biorheology of soft tissues. Biorheology 10:139–155, 1973.
Fung, Y. C. Biomechanics: Motion, Flow, Stress, and Growth. NY: Springer, 1990.
Fung, Y. C., K. Fronek, and P. Patitucci. Pseudoelasticity of arteries and the choice of its mathematical expression. Am. J. Physiol. Heart Circ. Physiol. 237:H620–H631, 1979.
Genovese, K., M. J. Collins, Y. U. Lee, and J. D. Humphrey. Regional finite strains in an angiotensin-II infusion model of dissecting abdominal aortic aneurysms. J. Cardiovasc. Eng. Tech. 3:194–202, 2012.
Gleason, R. L., W. W. Dye, E. Wilson, and J. D. Humphrey. Quantification of the mechanical behavior of carotid arteries from wild-type, dystrophin-deficient, and sarcoglycan-delta knockout mice. J. Biomech. 41:3213–3218, 2008.
Gleason, R. L., S. P. Gray, E. Wilson, and J. D. Humphrey. A multiaxial computer-controlled organ culture and biomechanical device for mouse carotid arteries. J. Biomech. Eng. 126:787–795, 2004.
Guo, X., and G. S. Kassab. Variation in mechanical properties along the length of the aorta in C57bl/6 mice. Am. J. Physiol. Heart Circ. Physiol. 285:H2614–H2622, 2003.
Guo, X., Y. Kono, R. Mattrey, and G. S. Kassab. Morphometry and strain distribution of the C57BL/6 mouse aorta. Am. J. Physiol. Heart Circ. Physiol. 283:H1829–H1837, 2002.
Hansen, L., W. Wan, and R. L. Gleason. Microstructurally motivated constitutive modeling of mouse arteries cultured under altered axial stretch. J. Biomech. Eng. 131:101015, 2009.
Hartner, A., L. Schaefer, M. Porst, N. Cordasic, A. Gabriel, B. Klanke, D. P. Reinhardt, and K. F. Hilgers. Role of fibrillin-1 in hypertensive and diabetic glomerular disease. Am. J. Physiol. Renal Physiol. 290:F1329–F1336, 2006.
Haskett, D., E. Speicher, M. Fouts, D. Larson, M. Azhar, U. Utzinger, and J. P. Vande Geest. The effects of angiotensin II on the coupled microstructural and biomechanical response of C57BL/6 mouse aorta. J. Biomech. 45:772–779, 2012.
Haskett, D., J. J. Doyle, C. Gard, H. Chen, C. Ball, M. A. Estabrook, A. C. Encinas, H. C. Dietz, U. Utzinger, J. P. Vande Geest, and M. Azhar. Altered tissue behavior of a non-aneurysmal descending thoracic aorta in the mouse model of Marfan syndrome. Cell Tissue Res. 347: 267–277, 2012.
Hayenga, H. N., J.-J. Hu, C. A. Meyer, E. Wilson, T. W. Hein, L. Kuo, and J. D. Humphrey. Differential progressive remodeling of coronary and cerebral arteries and arterioles in an aortic coarctation model of hypertension. Front. Physiol. 3:420, 2012.
Hayenga, H. N., A. Trache, J. Trzeciakowski, and J. D. Humphrey. Regional atherosclerotic plaque properties in ApoE−/− mice measured by atomic force, immunofluroescence, and light microscopy. J. Vasc. Res. 48:495–504, 2011.
Holzapfel, G. A. Determination of material models for arterial walls from uniaxial extension tests and histological structure. J. Theor. Biol. 238:290–302, 2006.
Holzapfel, G. A., T. C. Gasser, and R. W. Ogden. A new constitutive framework for arterial wall mechanics and a comparative study of material models. J. Elast. 61:1–48, 2000.
Holzapfel, G. A., G. Sommer, M. Auer, P. Regitnig, and R. W. Ogden. Layer-specific 3D residual deformations of human aortas with non-atherosclerotic intimal thickening. Ann. Biomed. Eng. 35:530–545, 2007.
Holzapfel, G. A., G. Sommer, C. T. Gasser, and P. Regitnig. Determination of layer-specific mechanical properties of human coronary arteries with nonatherosclerotic intimal thickening and related constitutive modeling. Am. J. Physiol. Heart Circ. Physiol. 289:H2048–H2058, 2005.
Hu, J.-J., A. Ambrus, T. W. Fossum, M. W. Miller, J. D. Humphrey, and E. Wilson. Time courses of growth and remodeling of porcine aortic media during hypertension: a quantitative immunohistochemical examination. J. Histochem. Cytochem. 56:359–370, 2008.
Humphrey, J. D. Stress, strain, and mechanotransduction in cells. J. Biomech. Eng. 123:638–641, 2001.
Humphrey, J. D. Vascular adaptation and mechanical homeostasis at tissue, cellular, and sub-cellular levels. Cell Biochem. Biophys. 50:53–78, 2008.
Humphrey, J. D. Mechanisms of arterial remodeling in hypertension: coupled roles of wall shear and intramural stress. Hypertension 52:195–200, 2008.
Humphrey, J. D. Cardiovascular Solid Mechanics. Cells, Tissues, and Organs. NY: Springer, 2002.
Humphrey, J. D., and S. L. Delange. An Introduction to Biomechanics: Solids and Fluids, Analysis and Design. NY: Springer, 2004.
Humphrey, J. D., J. F. Eberth, W. W. Dye, and R. L. Gleason. Fundamental role of axial stress in compensatory adaptations by arteries. J. Biomech. 42:1–8, 2009.
Humphrey, J. D., and K. R. Rajagopal. A constrained mixture model for growth and remodeling of soft tissues. Math. Model Methods Appl. Sci. 12:407–430, 2002.
Huo, Y., X. Guo, and G. S. Kassab. The flow field along the entire length of mouse aorta and primary branches. Ann. Biomed. Eng. 36:685–699, 2008.
Kanematsu, Y., M. Kanematsu, C. Kurihara, T.-L. Tsou, Y. Nuki, E. I. Liang, H. Makino, and T. Hashimoto. Pharmacologically induced thoracic and abdominal aortic aneurysms in mice. Hypertension 55:1267–1274, 2010.
Karšaj, I., J. Sorić, and J. D. Humphrey. A 3-D framework for arterial growth and remodeling in response to altered hemodynamics. Int. J. Eng. Sci. 48:1357–1372, 2010.
Kroon, M. A constitutive model for smooth muscle including active tone and passive viscoelastic behaviour. Math. Med. Biol. 27:129–155, 2010.
Lakatta, E. G., M. Wang, and S. S. Najjar. Arterial aging and subclinical arterial disease are fundamentally intertwined at macroscopic and microscopic levels. Med. Clin. N. Am. 93:583–604, 2009.
Mariko, B., M. Pezet, B. Escoubet, S. Bouillot, J.-P. Andrieu, B. Starcher, D. Quaglino, M.-P. Jacob, P. Huber, F. Ramirez, and G. Faury. Fibrillin-1 genetic deficiency leads to pathological ageing of arteries in mice. J. Pathol. 224:33–44, 2011.
Masson, I., P. Boutouyrie, S. Laurent, J. D. Humphrey, and M. Zidi. Characterization of arterial wall mechanical properties and stresses from human clinical data. J. Biomech. 41:2618–2627, 2008.
Matlung, H. L., A. E. Neele, H. C. Groen, K. van Gaalen, B. G. Tuna, A. van Weert, J. de Vos, J. J. Wentzel, M. Hoogenboezem, J. D. van Buul, E. Vanbavel, and E. N. T. P. Bakker. Transglutaminase activity regulates atherosclerotic plaque composition at locations exposed to oscillatory shear stress. Atherosclerosis 224:355–362, 2012.
Milewicz, D. M., D.-C. Guo, V. Tran-Fadulu, A. L. Lafont, C. L. Papke, S. Inamoto, C. S. Kwartler, and H. Pannu. Genetic basis of thoracic aortic aneurysms and dissections: focus on smooth muscle cell contractile dysfunction. Annu. Rev. Genomics Hum. Genet. 9:283–302, 2008.
Murtada, S.-I., M. Kroon, and G. A. Holzapfel. A calcium-driven mechanochemical model for prediction of force generation in smooth muscle. Biomech. Model. Mechanobiol. 9:749–762, 2010.
Ning, J., S. Xu, Y. Wang, S. M. Lessner, M. A Sutton, K. Anderson, and J. E. Bischoff. Deformation measurements and material property estimation of mouse carotid artery using a microstructure-based constitutive relation. J. Biomech. Eng. 132:121010, 2010.
Pezet, M., M.-P. Jacob, B. Escoubet, D. Gheduzzi, E. Tillet, P. Perret, P. Huber, D. Quaglino, R. Vranckx, D. Y. Li, B. Starcher, W. A. Boyle, R. P. Mecham, and G. Faury. Elastin haplo-insufficiency induces alternative aging processes in the aorta. Rejuvenation Res. 11:97–112, 2008.
Rachev, A., and K. Hayashi. Theoretical study of the effects of vascular smooth muscle contraction on strain and stress distributions in arteries. Ann. Biomed. Eng. 27:459–468, 1999.
Safar, M. E. Arterial aging—hemodynamic changes and therapeutic options. Nat. Rev. Cardiol. 7:442–449, 2010.
Sakalihasan, N., R. Limet, and O. D. Defawe. Abdominal aortic aneurysm. Lancet 365:1577–1589, 2005.
Schildmeyer, L. A., R. Braun, G. Taffet, M. Debiasi, A. E. Burns, A. Bradley, and R. J. Schwartz. Impaired vascular contractility and blood pressure homeostasis in the smooth muscle alpha-actin null mouse. FASEB J. 14:2213–2220, 2000.
Schriefl, A. J., G. Zeindlinger, D. M. Pierce, P. Regitnig, and G. A. Holzapfel. Determination of the layer-specific distributed collagen fibre orientations in human thoracic and abdominal aortas and common iliac arteries. J. R. Soc. Interface 9:1275–1286, 2012.
Sommer, G., and G. A. Holzapfel. 3D constitutive modeling of the biaxial mechanical response of intact and layer-dissected human carotid arteries. J. Mech. Behav. Biomed. Mater. 5:116–128, 2012.
Stålhand, J., A. Klarbring, and G. A. Holzapfel. A mechanochemical 3D continuum model for smooth muscle contraction under finite strains. J. Theor. Biol. 268:120–130, 2011.
Stevic, I., H. H. W. Chan, and A. K. C. Chan. Carotid artery dissections: thrombosis of the false lumen. Thromb. Res. 128:317–324, 2011.
Truesdell, C. and W. Noll. The nonlinear field theories of mechanics. In: Handbuch der Physik, edited by S. Flugge. Berlin: Springer, 1965.
Van Loon, P., W. Klip, and E. L. Bradley. Length-force and volume-pressure relationships of arteries. Biorheology 14:181–201, 1977.
Vande Geest, J. P., M. S. Sacks, and D. A. Vorp. Age dependency of the biaxial biomechanical behavior of human abdominal aorta. J. Biomech. Eng. 126:815–822, 2004.
Vande Geest, J. P., M. S. Sacks, and D. A. Vorp. A planar biaxial constitutive relation for the luminal layer of intra-luminal thrombus in abdominal aortic aneurysms. J. Biomech. 39:2347–2354, 2006.
Wagenseil, J. E., C. H. Ciliberto, R. H. Knutsen, M. A. Levy, A. Kovacs, and R. P. Mecham. Reduced vessel elasticity alters cardiovascular structure and function in newborn mice. Circ. Res. 104:1217–1224, 2009.
Wagenseil, J. E., and R. P. Mecham. Vascular extracellular matrix and arterial mechanics. Physiol. Rev. 89:957–989, 2009.
Wagenseil, J. E., N. L. Nerurkar, R. H. Knutsen, R. J. Okamoto, D. Y. Li, and R. P. Mecham. Effects of elastin haploinsufficiency on the mechanical behavior of mouse arteries. Am. J. Physiol. 289:H1209–H1217, 2005.
Wagner, H. P., and J. D. Humphrey. Differential passive and active biaxial mechanical behaviors of muscular and elastic arteries: basilar versus common carotid. J. Biomech. Eng. 133:051009, 2011.
Wan, W., J. B. Dixon, and R. L. Gleason. Constitutive modeling of mouse carotid arteries using experimentally measured microstructural parameters. Biophys. J. 102:2916–2925, 2012.
Wan, W., H. Yanagisawa, and R. L. Gleason. Biomechanical and microstructural properties of common carotid arteries from fibulin-5 null mice. Ann. Biomed. Eng. 38:3605–3617, 2010.
Weiszäcker, H. W., H. Lambert, and K. Pascale. Analysis of the passive mechanical properties of rat carotid arteries. J. Biomech. 16:703–715, 1983.
Wilson, J. S., S. Baek, and J. D. Humphrey. Importance of initial aortic properties on the evolving regional anisotropy, stiffness and wall thickness of human abdominal aortic aneurysms. J. R. Soc. Interface 9:2047–2058, 2012.
Xu, H., J.-J. Hu, J. D. Humphrey, and J.-C. Liu. Automated measurement and statistical modelling of elastic laminae in arteries. Comput. Methods Biomech. Biomed. Eng. 13:749–763, 2010.
Zeinali-Davarani, S., J. Choi, and S. Baek. On parameter estimation for biaxial mechanical behavior of arteries. J. Biomech. 42:524–530, 2009.
Acknowledgments
This work was supported, in part, by grants from the NIH (R01 HL-105297, R21 HL-107768). We are grateful for the insightful comments by the reviewers, which resulted in a significant revision to present more details on methods for testing and quantification that might help lead to increased standardization. JF and MRB thank Dr. Sara Roccabianca for providing an implementation of the theory of “small on large” that was integrated within our custom code for data analysis. JDH also acknowledges colleagues (Drs. Vince Gresham, Emily Wilson, and Alvin Yeh) and former students (Rudy L. Gleason, Ph.D., Wendy W. Dye, M.S., John F. Eberth, Ph.D., Heather N. Hayenga, Ph.D., Anne I. Taucer, M.S., and Melissa J. Collins, Ph.D) who contributed so much to this overall work on murine arterial mechanics and mechanobiology.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Additional information
Associate Editor Dan Elson oversaw the review of this article.
J. Ferruzzi and M. R. Bersi contributed equally to this work.
Rights and permissions
About this article
Cite this article
Ferruzzi, J., Bersi, M.R. & Humphrey, J.D. Biomechanical Phenotyping of Central Arteries in Health and Disease: Advantages of and Methods for Murine Models. Ann Biomed Eng 41, 1311–1330 (2013). https://doi.org/10.1007/s10439-013-0799-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10439-013-0799-1