Research Papers

Decreased Elastic Energy Storage, Not Increased Material Stiffness, Characterizes Central Artery Dysfunction in Fibulin-5 Deficiency Independent of Sex

[+] Author and Article Information
J. Ferruzzi, M. R. Bersi, S. Uman

Department of Biomedical Engineering,
Malone Engineering Center,
Yale University,
New Haven, CT 06520

H. Yanagisawa

Department of Molecular Biology,
University of Texas Southwestern
Medical Center,
Dallas, TX 75390

J. D. Humphrey

Fellow ASME
Department of Biomedical Engineering,
Malone Engineering Center,
Yale University,
New Haven, CT 06520
Vascular Biology and Therapeutics Program,
Yale School of Medicine,
New Haven, CT 06510
e-mail: jay.humphrey@yale.edu

1Corresponding author.

Manuscript received March 8, 2014; final manuscript received December 18, 2014; published online January 29, 2015. Assoc. Editor: Hai-Chao Han.

J Biomech Eng 137(3), 031007 (Mar 01, 2015) (14 pages) Paper No: BIO-14-1111; doi: 10.1115/1.4029431 History: Received March 08, 2014; Revised December 18, 2014; Online January 29, 2015

Central artery stiffness has emerged over the past 15 years as a clinically significant indicator of cardiovascular function and initiator of disease. Loss of elastic fiber integrity is one of the primary contributors to increased arterial stiffening in aging, hypertension, and related conditions. Elastic fibers consist of an elastin core and multiple glycoproteins; hence defects in any of these constituents can adversely affect arterial wall mechanics. In this paper, we focus on mechanical consequences of the loss of fibulin-5, an elastin-associated glycoprotein involved in elastogenesis. Specifically, we compared the biaxial mechanical properties of five central arteries—the ascending thoracic aorta, descending thoracic aorta, suprarenal abdominal aorta, infrarenal abdominal aorta, and common carotid artery—from male and female wild-type and fibulin-5 deficient mice. Results revealed that, independent of sex, all five regions in the fibulin-5 deficient mice manifested a marked increase in structural stiffness but also a marked decrease in elastic energy storage and typically an increase in energy dissipation, with all differences being most dramatic in the ascending and abdominal aortas. Given that the primary function of large arteries is to store elastic energy during systole and to use this energy during diastole to work on the blood, fibulin-5 deficiency results in a widespread diminishment of central artery function that can have significant effects on hemodynamics and cardiac function.

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Grahic Jump Location
Fig. 1

Pressure–diameter (P–d) and axial force–length (f–l) data (mean ± SEM) for all 20 groups (cf. Table 2): ATA, DTA, SAA, IAA, and CCA from male (M, black lines), female (F, gray lines), Fbln5+/+ (+/+, dashed lines), and Fbln5−/− (−/−, solid lines) mice. Each curve is the average of n = 5 experimental data sets. The first column shows video images of the central region of representative specimens under in vivo loads to highlight the different sizes. The second column shows P–d responses during inflation tests at the individual preferred values of axial stretch; note the different scales for the abscissas but the similar behaviors. The third column shows f–P responses during inflation tests, with force not changing much with pressurization as expected at the preferred value of axial stretch. Finally, the fourth column shows axial f–l responses during extension tests at 100 mmHg. Note the different scales for the ordinates in both the third and fourth columns, with overall lower forces exhibited by smaller arteries as expected.

Grahic Jump Location
Fig. 2

Average Cauchy stress–stretch responses calculated for all 20 groups (based on parameters in Table 3) by simulating P–d tests at the individual in vivo axial stretches (cf. Fig. 1). All data plotted using the same scale to facilitate visual comparisons. Notice the regionally consistent leftward shift in circumferential behavior and downward shift in axial behavior for Fbln5−/− (−/−, solid lines) mice relative to Fbln5+/+ (+/+, dashed lines). Results for stress (in kPa) and linearized stiffness (in MPa; see Table 2), the latter of which can be visualized by local tangents based on calculations via Eq. (5), were remarkably similar between males (M—black lines) and females (F—gray lines) in all tested regions.

Grahic Jump Location
Fig. 3

Average biaxial stiffness (mean ± SEM) in male (M, black bars), female (F, gray bars), Fbln5+/+ (+/+, shaded bars), and Fbln5−/− (−/−, solid bars) mice. (a) Circumferential stiffness of Fbln5−/− arteries was equal to or lower than wild-types. (b) Axial stiffness was similar between genotypes, independent of sex. Numerical values and significant differences with p < 0.05 are reported in Table 2.

Grahic Jump Location
Fig. 4

Average iso-energy contours of the stored energy calculated as a function of biaxial stretches W(λθ,λz). Fbln5+/+ are shown in the left column and Fbln5−/− in the right column; males are shown via black lines while females are shown via gray lines. Each panel shows energy levels corresponding to 0.1, 1, 5, 10, 20, 40, 60, 100, 250, and 500 kPa. Filled circles represent in vivo energy values computed at Psys and the individual in vivo axial stretches.

Grahic Jump Location
Fig. 5

Average energy storage and in vivo axial stretch (mean ± SEM) from male (M, black bars), female (F, gray bars), Fbln5+/+ (+/+, shaded bars), and Fbln5−/− (−/−, solid bars) mice. (a) Energy stored at individual Psys and in vivo axial stretches (cf. Fig. 4) was significantly higher in wild-type versus fibulin-5 deficient arteries for each region, independent of sex. (b) in vivo axial stretch ratio was consistently higher in wild-type arteries. Sex differences were observed in Fbln5+/+ IAAs (increased in females) and Fbln5−/− DTAs (decreased in females). Numerical values and significant differences with p < 0.05 are reported in Table 2.

Grahic Jump Location
Fig. 6

Microstructural composition of male Fbln5+/+ and Fbln5−/− arteries. (a) VVG-stained cross sections of central arteries from wild-type and fibulin-5 deficient animals. Note the generalized elastin (black) fragmentation and the loss of laminae waviness in the IAA and CCA of Fbln5−/− arteries. (b) MOV- and MTC-stained cross sections of ATAs showing collagen (blue in MTC), smooth muscle cytoplasm (red in MTC), and GAGs/PGs (blue–green in MOV). See on-line version for color. (c) and (d) Regional composition of Fbln5+/+ and Fbln5−/− arteries, respectively. Numerical values and significant differences with p < 0.05 are reported in Table 4.

Grahic Jump Location
Fig. 7

Structure–function relationship for Fbln5+/+ and Fbln5−/− arteries showing the uniform loss of functionality due to fibulin-5 deficiency. (a) Systolic stored energy is consistently decreased in Fbln5−/− arteries. (b) EDR is consistently increased in Fbln5−/− arteries.



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