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Research Papers

Elastic Fiber Fragmentation Increases Transmural Hydraulic Conductance and Solute Transport in Mouse Arteries

[+] Author and Article Information
Austin J. Cocciolone, Jin-Yu Shao

Department of Biomedical Engineering,
Washington University,
St. Louis, MO 63130

Elizabeth O. Johnson

Department of Mechanical Engineering and
Materials Science,
Washington University,
St. Louis, MO 63130

Jessica E. Wagenseil

Department of Mechanical Engineering and
Materials Science,
Washington University,
St. Louis, MO 63130
e-mail: jessica.wagenseil@wustl.edu

1Corresponding author.

Manuscript received August 3, 2018; final manuscript received November 12, 2018; published online December 19, 2018. Assoc. Editor: Seungik Baek.

J Biomech Eng 141(2), 021013 (Dec 19, 2018) (10 pages) Paper No: BIO-18-1352; doi: 10.1115/1.4042173 History: Received August 03, 2018; Revised November 12, 2018

Transmural advective transport of solute and fluid was investigated in mouse carotid arteries with either a genetic knockout of fibulin-5 (Fbln5−/−) or treatment with elastase to determine the influence of a disrupted elastic fiber matrix on wall transport properties. Fibulin-5 is an important director of elastic fiber assembly. Arteries from Fbln5−/− mice have a loose, noncontinuous elastic fiber network and were hypothesized to have reduced resistance to advective transport. Experiments were carried out ex vivo at physiological pressure and axial stretch. Hydraulic conductance (LP) was measured to be 4.99 × 10−6±8.94 × 10−7, 3.18−5±1.13 × 10−5 (p < 0.01), and 3.57 × 10−5 ±1.77 × 10−5 (p < 0.01) mm·s−1·mmHg−1 for wild-type, Fbln5−/−, and elastase-treated carotids, respectively. Solute fluxes of 4, 70, and 150 kDa fluorescein isothiocyanate (FITC)-dextran were statistically increased in Fbln5−/− compared to wild-type by a factor of 4, 22, and 3, respectively. Similarly, elastase-treated carotids demonstrated a 27- and 13-fold increase in net solute flux of 70 and 150 kDa FITC-dextran, respectively, compared to untreated carotids, and 4 kDa FITC-dextran was unchanged between these groups. Solute uptake of 4 and 70 kDa FITC-dextran within Fbln5−/− carotids was decreased compared to wild-type for all investigated time points. These changes in transport properties of elastic fiber compromised arteries have important implications for the kinetics of biomolecules and pharmaceuticals in arterial tissue following elastic fiber degradation due to aging or vascular disease.

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Figures

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Fig. 1

Representative histological cross section of Fbln5+/+ (a), Fbln5−/− (b), and elastase-treated Fbln5+/+ (c) carotid arteries. The elastic lamellae are colored black by the VVG stain. The arterial lumen (L) is toward the bottom of the images. Phenotypic over-deposition and under-deposition of elastin within the elastic lamellae of Fbln5−/− are indicated by blue, upward-facing arrows and green, downward-facing arrows, respectively. The scale bar indicates 20 μm. Please see online version for color images.

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Fig. 2

Representative two-photon microscopy images of elastin auto fluorescence from en face Fbln5+/+ (a and d), Fbln5−/− (b and e), and elastase-treated Fbln5+/+ ((c) and (f)) carotids. Panels (a, b, and c) are views of a single plane from the z-stack within the internal elastic lamella. Orthogonal views of the z-stack are shown next to Panels a, b, and c for three-dimensional visualization. The orientation for each image is indicated (circ = circumferential, long = longitudinal, rad = radial). The yellow lines represent the image location within the z-stack. The red scale bar (top) indicates 50 μm. Panels d, e, and f are magnified z-projections of four consecutive planes from the z-stack within the internal elastic lamella. Blue, upward facing arrows indicate a fenestration (hole) within the elastic lamina. Green, downward facing arrows show the elastic lamella undulating out of the z-projection plane. The yellow scale bar (bottom) indicates 10 μm. Please see online version for color images.

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Fig. 3

Results from the volumetric fluid flux experiments. Panel a—the displacement of the tracking bubble over time for each of the tissues. Error bars are standard error of the mean (SEM) for clarity. Panel b—hydraulic conductance of Fbln5+/+ (n = 7), Fbln5−/− (n = 8), and elastase-treated Fbln5+/+ carotids (n = 8). Error bars are SD. Statistical significance was determined between Fbln5+/+ and Fbln5−/− (*p = 0.0021) and between Fbln5+/+ and elastase-treated Fbln5+/+ (†p = 0.0004).

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Fig. 4

Results from the net solute flux experiments. The change in solute concentration in the external bath with time for the 4, 70, and 150 kDa FITC-dextrans are shown in panels a, b, and c, respectively (n = 5–9). Error bars are SEM for clarity. Panel d—the net solute flux across the carotid wall of the investigated dextran sizes on a semilog plot. Statistical significance between Fbln5+/+ and Fbln5−/− (*), Fbln5+/+ and elastase-treated Fbln5+/+ (†), and Fbln5+/+ and elastase-treated Fbln5+/+ (#) are indicated. Error bars are SD.

Grahic Jump Location
Fig. 5

Results from the solute uptake experiments. Quantity of 4 kDa (a) and 70 kDa (b) FITC-dextran retained within the wall of the Fbln5+/+ and Fbln5−/− carotids after 30, 60, 120, and 240 min (n = 6–7). The value is normalized to the length of the artery. Statistical significance between Fbln5+/+ and Fbln5−/− (*) was determined at the indicated dextran size and time. Error bars are SEM for clarity. Panel c—isolated results at 60 min including 150 kDa FITC-dextran and elastase-treated artery experiments. Statistical significance between Fbln5+/+ and Fbln5−/− (*), Fbln5+/+ and elastase-treated Fbln5+/+ (†), and Fbln5+/+ and elastase-treated Fbln5+/+ (#) are indicated. Error bars are SD.

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