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Research Papers

Amyloid Beta Influences Vascular Smooth Muscle Contractility and Mechanoadaptation

[+] Author and Article Information
Eric S. Hald

Department of Biomedical Engineering,
University of Minnesota,
7-105 Nils Hasselmo Hall,
312 Church Street SE,
Minneapolis, MN 554555
e-mail: haldx002@umn.edu

Connor D. Timm

Department of Biomedical Engineering,
University of Minnesota,
7-105 Nils Hasselmo Hall,
312 Church Street SE,
Minneapolis, MN 554555
e-mail: timmx182@umn.edu

Patrick W. Alford

Department of Biomedical Engineering,
University of Minnesota,
7-105 Nils Hasselmo Hall,
312 Church Street SE,
Minneapolis, MN 554555
e-mail: pwalford@umn.edu

1Corresponding author.

Manuscript received May 27, 2016; final manuscript received August 17, 2016; published online October 21, 2016. Assoc. Editor: Jessica E. Wagenseil.

J Biomech Eng 138(11), 111007 (Oct 21, 2016) (8 pages) Paper No: BIO-16-1226; doi: 10.1115/1.4034560 History: Received May 27, 2016; Revised August 17, 2016

Amyloid beta accumulation in neuronal and cerebrovascular tissue is a key precursor to development of Alzheimer's disease and can result in neurodegeneration. While its persistence in Alzheimer's cases is well-studied, amyloid beta's direct effect on vascular function is unclear. Here, we measured the effect of amyloid beta treatment on vascular smooth muscle cell functional contractility and modeled the mechanoadaptive growth and remodeling response to these functional perturbations. We found that the amyloid beta 1-42 isoform induced a reduction in vascular smooth muscle cell mechanical output and reduced response to vasocontractile cues. These data were used to develop a thin-walled constrained mixture arterial model that suggests vessel growth, and remodeling in response to amyloid betamediated alteration of smooth muscle function leads to decreased ability of cerebrovascular vessels to vasodilate. These findings provide a possible explanation for the vascular injury and malfunction often associated with the development of neurodegeneration in Alzheimer's disease.

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Figures

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Fig. 1

Schematic of growth and remodeling in thin-walled, constrained mixture arterial model. All the constituents (elastin: left collagen: middle, and muscle cells: right) undergo deformation F, transitioning the artery from a loaded reference configuration, b(0), to a loaded current configuration, b(t). While the constituents are constrained to move together, their zero-stress configurations evolve separately, yielding different elastic deformations for each component. Zero-stress configurations are denoted by capital Bs. Elastin and collagen are produced and degraded with time, with insertion at a prescribed initial stretch ratio, λoe or λoc. Deformation from the zero-stress configuration, Be or Bc, to the current configuration is denoted by the elastic deformation gradient tensor, F*e or F*c. Muscle cells undergo stress-free deformation due to growth, G, and active contraction, A. Upon reassembly and vessel loading, there is an elastic deformation, F*m, from the zero-stress actively contracted state which encompasses growth and active contraction, Bam, to the current configuration, b(t).

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Fig. 2

Treatment of VSMCs with Aβ yields differences in Aβ plaque formation and nuclear morphology. (a) Representative immunofluorescent images of single VSMCs for different treatment conditions; blue: DAPI-stained nuclei, phalloidin-stained f-actin, and immunostained Aβ fibrils; scale bar: 25 μm. (b) (i) Traced VSMC for Aβ plaque coverage quantification, (ii) isolation of VSMC area in Aβ-stained image, and (iii) thresholded Aβ signal for particle analysis. (c) Aβ plaque coverage after 24 h of treatment; error bars: standard deviation and *: significant difference, p < 0.05. (d) Cell spread area after 24 h of Aβ treatment; error bars: standard deviation. (e) VSMC nuclear eccentricity after 24 h of Aβ treatment; boxes: 25–75%, whiskers: 10–90%, mean and median lines shown.

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Fig. 3

Amyloid beta influences VSMC basal functional contractility. (a) Representative brightfield image of VSMC on PA gel, scale bar: 100 μm. (b) Heat map of measured substrate displacement resulting from VSMC traction. (c)–(e) Basal strain energy exerted by cells treated for 24 h (c), 48 h (d), and 96 h (e) with Aβ 1-42. (f) ET-1-induced contraction strain energy following 24 h treatment with Aβ; *: significant difference, p < 0.05.

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Fig. 5

Thin-walled constrained mixture collagen deposition model of cerebrovascular response to altered target stress. (a) Vessel wall thickness and volume fractions of collagen (ϕc) and VSMCs (ϕm). (b) Circumferential growth stretch ratio, λgθ, and radial growth stretch ratio, λgr, relative to baseline homeostatic conditions (σo=75 kPa). (c) Pressure–radius curves for active (solid lines) and passive (dashed lines) mechanical responses for specified target stress. (d) Vasodilation, represented as the ratio between the passive vessel radius, rpassive, and the active vessel radius, ractive, as a function of target stress.

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Fig. 6

Loss of VSMC ability to actively contract attenuates vasodilation in model vessels. (a) Pressure–radius curves for active (solid lines) and passive (dashed lines) mechanical responses for specified homeostatic active stretch ratio and target stress σo=75 kPa. (b) Vasodilation, represented as the ratio between the passive vessel radius, rpassive, and the active vessel radius, ractive, as a function of changes in the active stretch ratio, λao, for specified target stress.

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Fig. 4

Thin-walled constrained mixture total growth model of cerebrovascular response to altered target stress. (a) Vessel wall thickness and volume fractions of collagen (ϕc) and VSMCs (ϕm). (b) Circumferential growth stretch ratio, λgθ, and radial growth stretch ratio, λgr, relative to baseline homeostatic conditions (σo=75 kPa). (c) Pressure–radius curves for active (solid lines) and passive (dashed lines) mechanical responses for specified target stress. (d) Vasodilation, represented as the ratio between the passive vessel radius, rpassive, and the active vessel radius, ractive, as a function of target stress.

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