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Research Papers

Reduced Biaxial Contractility in the Descending Thoracic Aorta of Fibulin-5 Deficient Mice

[+] Author and Article Information
S.-I. Murtada

Department of Biomedical Engineering,
Yale University,
New Haven, CT 06520;
Department of Physiology and Pharmacology,
Karolinska Institutet,
Stockholm 17177, Sweden
e-mail: sae-il.murtada@yale.edu

J. Ferruzzi

Department of Biomedical Engineering,
Yale University,
New Haven, CT 06520
e-mail: jacopo.ferruzzi@yale.edu

H. Yanagisawa

Life Science Center,
Tsukuba Advanced Research Alliance,
University of Tsukuba,
Ibaraki 305-8577, Japan
e-mail: hkyanagisawa@tara.tsukuba.ac.jp

J. D. Humphrey

Fellow ASME
Department of Biomedical Engineering,
Yale University,
New Haven, CT 06520
e-mail: jay.humphrey@yale.edu

1Corresponding author.

Manuscript received September 21, 2015; final manuscript received February 17, 2016; published online March 30, 2016. Assoc. Editor: Jonathan Vande Geest.

J Biomech Eng 138(5), 051008 (Mar 30, 2016) (7 pages) Paper No: BIO-15-1474; doi: 10.1115/1.4032938 History: Received September 21, 2015; Revised February 17, 2016

The precise role of smooth muscle cell contractility in elastic arteries remains unclear, but accumulating evidence suggests that smooth muscle dysfunction plays an important role in the development of thoracic aortic aneurysms and dissections (TAADs). Given the increasing availability of mouse models of these conditions, there is a special opportunity to study roles of contractility ex vivo in intact vessels subjected to different mechanical loads. In parallel, of course, there is a similar need to study smooth muscle contractility in models that do not predispose to TAADs, particularly in cases where disease might be expected. Multiple mouse models having compromised glycoproteins that normally associate with elastin to form medial elastic fibers present with TAADs, yet those with fibulin-5 deficiency do not. In this paper, we show that deletion of the fibulin-5 gene results in a significantly diminished contractility of the thoracic aorta in response to potassium loading despite otherwise preserved characteristic active behaviors, including axial force generation and rates of contraction and relaxation. Interestingly, this diminished response manifests around an altered passive state that is defined primarily by a reduced in vivo axial stretch. Given this significant coupling between passive and active properties, a lack of significant changes in passive material stiffness may help to offset the diminished contractility and thereby protect the wall from detrimental mechanosensing and its sequelae.

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References

Yanagisawa, H. , Davis, E. C. , Starcher, B. C. , Ouchi, T. , Yanagisawa, M. , Richardson, J. A. , and Olson, E. N. , 2002, “ Fibulin-5 is an Elastin-Binding Protein Essential for Elastic Fiber Development In Vivo,” Nature, 415(6868), pp. 168–171. [CrossRef] [PubMed]
Le, V . P. , Cheng, J. K. , Kim, J. , Staiculescu, M. C. , Ficker, S. W. , Sheth, S. C. , Bhayani, S. A. , Mecham, R. P. , Yanagisawa, H. , and Wagenseil, J. E. , 2015, “ Mechanical Factors Direct Mouse Aortic Remodeling During Early Maturation,” J. R. Soc. Interface., 12(104), p. 20141350. [CrossRef] [PubMed]
Ferruzzi, J. , Bersi, M. R. , Uman, S. , Yanagisawa, H. , and Humphrey, J. D. , “ Decreased Energy Storage, Not Increased Material Stiffness, Characterizes Central Artery Dysfunction in Fibulin-5 Deficiency Independent of Sex,” ASME J. Biomech. Eng., 137(3), p. 031007. [CrossRef]
Pereira, L. , Lee, S. Y. , Gayraud, B. , Andrikopoulos, K. , Shapiro, S. D. , Bunton, T. , Biery, N. J. , Dietz, H. C. , Sakai, L. Y. , and Ramirez, F. , 1999, “ Pathogenetic Sequence for Aneurysm Revealed in Mice Under Expressing Fibrillin-1,” Proc. Natl. Acad. Sci. USA, 96(7), pp. 3819–3823. [CrossRef]
Huang, J. , Davis, E. C. , Chapman, S. L. , Budatha, M. , Marmorstein, L. Y. , Word, R. A. , and Yanagisawa, H. , 2010, “ Fibulin-4 Deficiency Results in Ascending Aortic Aneurysms: A Potential Link Between Abnormal Smooth Muscle Cell Phenotype and Aneurysm Progression,” Circ. Res., 106(3), pp. 583–592. [CrossRef] [PubMed]
Wang, X. , LeMaire, S. A. , Chen, L. , Carter, S. A. , Shen, Y. H. , Gan, Y. , Bartsch, H. , Wilks, J. A. , Utama, B. , Ou, H. , Thompson, R. W. , Coselli, J. S. , and Wang, X. L. , 2005, “ Decreased Expression of Fibulin-5 Correlates With Reduced Elastin in Thoracic Aortic Dissection,” Surgery, 138(2), pp. 352–359. [CrossRef] [PubMed]
Humphrey, J. D. , Schwartz, M. A. , Tellides, G. , and Milewicz, D. M. , 2015, “ Role of Mechanotransduction in Vascular Biology: Focus on Thoracic Aortic Aneurysms and Dissections,” Circ. Res., 116(8), pp. 1448–1461. [CrossRef] [PubMed]
Kim, H. R. , Appel, S. , Betterkind, S. , Gangopadhyay, S. S. , and Morgan, K. G. , 2008, “ Smooth Muscle Signaling Pathways in Health and Disease,” J. Cell. Mol. Med., 12(6a), pp. 2165–2180. [CrossRef] [PubMed]
Putz, S. , Lubomirov, L. T. , and Pfitzer, G. , 2009, “ Regulation of Smooth Muscle Contraction by Small GTPases,” Physiology, 24(6), pp. 324–356.
Ferruzzi, J. , Bersi, M. R. , and Humphrey, J. D. , 2013, “ Biomechanical Phenotyping of Central Arteries in Health and Disease: Advantages of and Methods for Murine Models,” Ann. Biomed. Eng., 41(7), pp. 1311–1330. [CrossRef] [PubMed]
Gleason, R. L. , Gray, S. P. , Wilson, E. , and Humphrey, J. D. , 2004, “ A Multiaxial Computer-Controlled Organ Culture and Biomechanical Device for Mouse Carotid Arteries,” ASME J. Biomech. Eng., 126(6), pp. 787–795. [CrossRef]
Agianniotis, A. , Rachev, A. , and Stergiopulos, N. , 2012, “ Active Axial Stress in Mouse Aorta,” J. Biomech., 26(45), pp. 1924–1927. [CrossRef]
Humphrey, J. D. , 2002, Cardiovascular Solid Mechanics: Cells, Tissues, and Organs, Springer, New York.
Wagner, H. P. , and Humphrey, J. D. , 2011, “ Differential Passive and Active Biaxial Mechanical Behaviors of Muscular and Elastic Arteries: Basilar Versus Common Carotid,” ASME J. Biomech. Eng., 133(5), p. 051009. [CrossRef]
Van Loon, P. , Klip, W. , and Bradley, E. L. , 1977, “ Length-Force and Volume–Pressure Relationships of Arteries,” Biorheology, 14(4), pp. 181–201. [PubMed]
Dobrin, P. B. , Schwarcz, T. H. , and Mrkvicka, R. , 1990, “ Longitudinal Retractive Force in Pressurized Dog and Human Arteries,” J. Surg. Res., 48(2), pp. 116–120. [CrossRef] [PubMed]
Humphrey, J. D. , Eberth, J. F. , Dye, W. W. , and Gleason, R. L. , 2009, “ Fundamental Role of Axial Stress in Compensatory Adaptations by Arteries,” J. Biomech., 42(1), pp. 1–8. [CrossRef] [PubMed]
Dye, W. W. , Gleason, R. L. , Wilson, E. , and Humphrey, J. D. , 2007, “ Altered Biomechanical Properties of Carotid Arteries in Two Mouse Models of Muscular Dystrophy,” J. Appl. Physiol., 103(2), pp. 664–672. [CrossRef] [PubMed]
Humphrey, J. D. , and Na, S. , 2002, “ Elastodynamics and Arterial Wall Stress,” Ann. Biomed. Eng., 30(4), pp. 509–523. [CrossRef] [PubMed]
Zulliger, M. A. , Kwak, N. T. , Tsapikouni, T. , and Stergiopulos, N. , 2002, “ Effects of Longitudinal Stretch on VSM Tone and Distensibility of Muscular Conduit Arteries,” Am. J. Physiol. Heart Circ. Physiol., 283(6), pp. H2599–H2605. [CrossRef] [PubMed]
Knapp, J. , Aleth, S. , Balzer, F. , Gergs, U. , Schmitz, W. , and Neumann, J. , 2006, “ Comparison of Contractile Responses in Isolated Mouse Aorta and Pulmonary Artery: Influence of Strain and Sex,” J. Cardiovasc. Pharmacol., 48(1), pp. 820–826. [CrossRef] [PubMed]
Cyron, C. , and Humphrey, J. D. , 2015, “ Preferred Fiber Orientations in Healthy Arteries and Veins Understood from Netting Analysis,” Math. Mech. Solids., 20(6), pp. 680–696. [CrossRef]
Humphrey, J. D. , and Wilson, E. , 2003, “ A Potential Role of Smooth Muscle Tone in Early Hypertension: A Theoretical Study,” J. Biomech., 36(11), pp. 1595–1601. [CrossRef] [PubMed]
Takamizawa, K. , Hayashi, K. , and Matsuda, T. , 1992, “ Isometric Biaxial Tension of Smooth Muscle in Isolated Cylindrical Segments of Rabbit Arteries,” Am. J. Physiol., 263(1), pp. H30–H34. [PubMed]
Humphrey, J. D. , 2003, “ Continuum Thermomechanics and the Treatment of Disease and Injury,” ASME Appl. Mech. Rev., 56(2), pp. 231–260. [CrossRef]
Murtada, S. -I. , Kroon, M. , and Holzapfel, G. A. , 2010, “ A Calcium-Driven Mechanochemical Model for Prediction of Force Generation in Smooth Muscle,” Biomech. Model. Mechanobiol., 9(6), pp. 749–762. [CrossRef] [PubMed]
Murtada, S.-I. , Arner, A. , and Holzapfel, G. A. , 2012, “ Experiments and Mechanochemical Modeling of Smooth Muscle Contraction: Significance of Filament Overlap,” J. Theor. Biol., 297, pp. 176–186. [CrossRef] [PubMed]
Murtada, S. -I. , Lewin, S. , Arner, A. , and Humphrey, J. D. , “ Adaptation of Active Tone in the Mouse Descending Thoracic Aorta Under Acute Changes in Loading,” Biomech. Model. Mechanobiol. (in press).
Milewicz, D. M. , Gou, D. C. , Fadulu, V. T. , Lafont, A. L. , Papke, C. L. , Inamoto, S. , Kwartler, C. S. , and Pannu, H. , 2008, “ Genetic Basis of Thoracic Aortic Aneurysms and Dissections: Focus on Smooth Muscle Cell Contractile Dysfunction,” Annu. Rev. Genomics. Hum. Genet., 9(1), pp. 283–302. [CrossRef] [PubMed]
Ferruzzi, J. , Murtada, S.-I. , Li, G. , Jiao, Y. , Uman, S. , Ting, M. Y.-L. , Tellides, G. , and Humphrey, J. D. , 2016, “ Pharmacologically Improved Contractility Protects Against Aortic Dissection in Mice With Disrupted TGFb Signaling Despite Compromised ECM Properties,” Arterioscl. Thromb. Vasc. Biol. (in press).

Figures

Grahic Jump Location
Fig. 1

Illustrative images captured with the video microscope of a Fbln5+/+ descending thoracic aorta (DTA) loaded at 90 mmHg and an axial stretch of λz=1.5 both before (top) and after (bottom) 15 min of exposure to 80 mM KCl. Similar, though diminished, responses were observed in Fbln5−/− specimens. The vertical line shows the region where outer diameter and wall thickness were measured; the horizontal dashed lines in the bottom image represent the outer diameter before exposure to high KCl. Note the ligated intercostal branches as well as the glass cannulae and ligatures used to secure the sample.

Grahic Jump Location
Fig. 2

Illustrative time courses of change in outer diameter measured with the video microscope (do—top panels), axial force measured by the force transducer (fT—middle panels), and wall thickness measured with the OCT (h—bottom panels), all when contracted with 80 mM KCl at 90 mmHg for Fbln5+/+ (left) and Fbln5−/− (right) DTAs at genotype-specific values of axial stretch: λz=1.40, 1.50, and 1.60 for Fbln5+/+ and λz=1.25, 1.30, and 1.35 for Fbln5−/−. Recall that contraction was maintained at each condition for ∼15 min prior to a wash-out with normal Krebs solution. The vertical dashed lines delineate changes in the different fixed values of axial stretch; the dark dashed arrows illustrate, for a single case, the magnitude and direction of contraction-induced changes in outer diameter and axial force that are considered in Fig. 3.

Grahic Jump Location
Fig. 3

Changes, relative to genotype-specific baseline values, in outer diameter (Δdo—top) and axial force (ΔfT—bottom) after 15 min of high K+ contraction at 70 (circle), 90 (triangle), and 110 (square) mmHg and different values of axial stretch: λz=1.25, 1.30, and 1.35 for Fbln5−/− (dashed line) and λz=1.40−1.45, 1.50, and 1.60 for Fbln5+/+ mice (solid line)

Grahic Jump Location
Fig. 4

Circumferential (top and middle) and axial (bottom) Cauchy stress–stretch relationships for both the contracted (black circle) and relaxed (gray square) states for Fbln5+/+ (solid symbols) and Fbln5−/− (open symbols) groups and at the studied pressures and axial stretches. The direction of changes in Cauchy stresses (Δσϑ,Δσz) and stretch (Δλϑ) due to isobaric and axially isometric contraction are marked with black arrows.

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