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Research Papers

Empirically Determined Vascular Smooth Muscle Cell Mechano-Adaptation Law

[+] Author and Article Information
Kerianne E. Steucke

Department of Biomedical Engineering,
University of Minnesota Twin Cities,
312 Church Street SE NHH 7-105,
Minneapolis, MN 55455
e-mail: steu0057@umn.edu

Zaw Win

Department of Biomedical Engineering, University of Minnesota Twin Cities,
312 Church Street SE NHH 7-105,
Minneapolis, MN 55455
e-mail: winxx005@umn.edu

Taylor R. Stemler

Department of Biomedical Engineering,
University of Minnesota Twin Cities,
312 Church Street SE NHH 7-105,
Minneapolis, MN 55455
e-mail: steml002@umn.edu

Emily E. Walsh

Department of Biomedical Engineering,
University of Minnesota Twin Cities,
312 Church Street SE NHH 7-105,
Minneapolis, MN 55455
e-mail: walsh553@umn.edu

Jennifer L. Hall

Division of Cardiology,
Department of Medicine,
University of Minnesota Twin Cities,
2231 6th Street SE CCRB,
Minneapolis, MN 55455
e-mail: jlhall@umn.edu

Patrick W. Alford

Department of Biomedical Engineering,
University of Minnesota Twin Cities,
312 Church Street SE NHH 7-105,
Minneapolis, MN 55455
e-mail: pwalford@umn.edu

1Corresponding author.

Manuscript received December 1, 2016; final manuscript received March 20, 2017; published online June 6, 2017. Assoc. Editor: Kristen Billiar.

J Biomech Eng 139(7), 071005 (Jun 06, 2017) (9 pages) Paper No: BIO-16-1491; doi: 10.1115/1.4036454 History: Received December 01, 2016; Revised March 20, 2017

Cardiovascular disease can alter the mechanical environment of the vascular system, leading to mechano-adaptive growth and remodeling. Predictive models of arterial mechano-adaptation could improve patient treatments and outcomes in cardiovascular disease. Vessel-scale mechano-adaptation includes remodeling of both the cells and extracellular matrix. Here, we aimed to experimentally measure and characterize a phenomenological mechano-adaptation law for vascular smooth muscle cells (VSMCs) within an artery. To do this, we developed a highly controlled and reproducible system for applying a chronic step-change in strain to individual VSMCs with in vivo like architecture and tracked the temporal cellular stress evolution. We found that a simple linear growth law was able to capture the dynamic stress evolution of VSMCs in response to this mechanical perturbation. These results provide an initial framework for development of clinically relevant models of vascular remodeling that include VSMC adaptation.

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Figures

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Fig. 1

Mechanical perturbation of micropatterned VSMCs: (a) schematic view of chronic strain traction force microscopy system. The micropatterned VSMC is seeded onto a fibronectin island printed onto a fluorescent bead-doped polyacrylamide gel bonded to an elastic membrane. (b) Custom steel clamps secure the elastomer membrane and apply the chronic strain to the VSMC micropatterned on the bead-doped polyacrylamide gel. (c) Measured elastomer membrane strain in the axial, εx, and transverse, εy, direction for each corresponding grip strain. Ideal measured strain to grip strain behavior for axial and transverse strain is represented by a solid line. (Mean±standard deviation). (d) (Top) Bright field images of representative cells prestrain and poststrain (20% applied chronic strain). Black arrow indicates direction of applied strain. Scale bar: 25 μm. (Middle) The corresponding substrate displacement. (Bottom) The corresponding cell traction stress heat maps. (e) Schematic of a single-cell force balance demonstrating that the midplane cell Cauchy stress (σx) multiplied by the cell cross-sectional area (Ax) is balanced by the axial cell traction forces (fx).

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Fig. 2

Growth and remodeling theory schematic. A single cell is shown in both the stressed and stress-free state as denoted by lower case bs and capitol Bs, respectively. Time zero refers to prestretch and time t refers to poststretch. The deformation gradient tensors, elastic deformation tensors, and growth tensors are represented by F, F*, and G, respectively. See text for details.

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Fig. 3

Temporal single-cell traction force response to applied chronic strain: (a) bright field images of a representative micropatterned VSMC at 0%, 10%, 20%, and 30% applied chronic strain. Dashed lines identify the cell edge. Scale bar: 25 μm. (b) Average single-cell axial traction stress heat maps for cells with 0%, 10%, 20%, and 30% applied strain at 0 h, 4 h, 8 h, and 24 h time points (n = 19–92). (c) Total axial traction force (fx) for VSMCs exposed to 0%, 10%, 20%, and 30% strain. (Mean±standard deviation). (d) Total transverse traction force (fy) for cells exposed to 0%, 10%, 20%, and 30% strain. (Mean±standard deviation). For (c) and (d), two-way ANOVA (factors: time and strain) was used to analyze data. * indicates statistical significance between marked strain and the strain indicated by the * shade (p < 0.01).

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Fig. 4

Cellular architecture: (a) immunofluorescent F-actin images of a representative micropatterned VSMC at 0%, 10%, 20%, and 30% applied chronic strain. Scale bar: 25 μm. (b) Mean cell thickness heat maps for cells with 0%, 10%, 20%, and 30% applied strain at 0 h, 4 h, 8 h, and 24 h time points (n = 8–11). (c) Poststrain axial cell cross-sectional area (Ax) (mean±standard deviation) (n = 8–11). (d) Poststrain transverse cell cross-sectional area (Ay) (mean±standard deviation) (n = 8–11). (e) Poststrain cell volume (mean±standard deviation) (n = 8–11). (f) Poststrain actin alignment described with an OOP. Note that an OOP value of one represents perfect alignment, while an OOP value of zero represents no alignment. (Mean±standard deviation) (n = 8–28). For (c)–(f), two-way ANOVA (factors: time and strain) was used to analyze data. * indicates statistical significance between marked strain and the strain indicated by the * shade (p < 0.02).

Grahic Jump Location
Fig. 5

Temporal cellular stress evolution. (a) VSMC midplane axial Cauchy stress following a chronic step-change applied strain. Cauchy stress was calculated from experimental traction forces and cellular architecture (n = 19–92). (Mean±standard deviation). * indicates statistical significance between marked data and data corresponding to the * shade within the same time point (p < 0.05). (b) VSMC midplane transverse Cauchy stress following a chronic step-change applied strain. Cauchy stress was calculated from experimental traction forces and cellular architecture (n = 19–92). (Mean±standard deviation). No statistical significance was found between strains at the same time point. (c) Temporal axial cell Cauchy stress for individual cells after 0% applied strain. Bold line is the data average. (d) Temporal axial cell Cauchy stress for individual cells after 10% applied strain. Bold line is the data average. (e) Temporal axial cell Cauchy stress for individual cells after 20% applied strain. Bold line is the data average. (f) Temporal axial cell Cauchy stress for individual cells after 30% applied strain. Bold line is the data average.

Grahic Jump Location
Fig. 6

Vascular smooth muscle cell mechano-adaptation law. (a) Mechano-adaptation law generated by the growth model to describe poststrain temporal stress evolution (experimental data: translucent data points). Target stress (σo) is represented by the line at 9.7 kPa. (b) Axial growth stretch ratio (λgx) for 10%, 20%, and 30% applied strain. (c) Transverse growth stretch ratio (λgy,λgz) for 10%, 20%, and 30% applied strain. (d) Axial stretch ratio (λx) (solid line) and axial elastic stretch ratio (λx*) (dashedline) for 10%, 20%, and 30% applied strain. (e) Transverse stretch ratio (λy, λz) (solid line) and transverse elastic stretch ratio (λy*,  λz*) (dashed line) for 10%, 20%, and 30% applied strain. Note that solid and dashed lines are nearly coincident.

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