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Research Papers

Quantification of Morphological Modulation, F-Actin Remodeling, and PECAM-1 (CD-31) Redistribution in Endothelial Cells in Response to Fluid-Induced Shear Stress Under Various Flow Conditions

[+] Author and Article Information
Hamed Avari

Advanced Fluid Mechanics Research Group,
Department of Mechanical and
Materials Engineering,
University of Western Ontario,
London, ON N6A 3K7, Canada
e-mail: havari@uwo.ca

Kem A. Rogers

Department of Anatomy and Cell Biology,
University of Western Ontario,
London, ON N6A 3K7, Canada
e-mail: kem.rogers@schulich.uwo.ca

Eric Savory

Advanced Fluid Mechanics Research Group,
Department of Mechanical and
Materials Engineering,
University of Western Ontario,
London, ON N6A 3K7, Canada
e-mail: esavory@uwo.ca

1Corresponding author.

Manuscript received December 21, 2017; final manuscript received January 4, 2019; published online February 15, 2019. Assoc. Editor: Nathan Sniadecki.

J Biomech Eng 141(4), 041004 (Feb 15, 2019) (12 pages) Paper No: BIO-17-1598; doi: 10.1115/1.4042601 History: Received December 21, 2017; Revised January 04, 2019

Cardiovascular diseases (CVDs) are the number one cause of death globally. Arterial endothelial cell (EC) dysfunction plays a key role in many of these CVDs, such as atherosclerosis. Blood flow-induced wall shear stress (WSS), among many other pathophysiological factors, is known to significantly contribute to EC dysfunction. The present study reports an in vitro investigation of the effect of quantified WSS on ECs, analyzing the EC morphometric parameters and cytoskeletal remodeling. The effects of four different flow cases (low steady laminar (LSL), medium steady laminar (MSL), nonzero-mean sinusoidal laminar (NZMSL), and laminar carotid (LCRD) waveforms) on the EC area, perimeter, shape index (SI), angle of orientation, F-actin bundle remodeling, and platelet endothelial cell adhesion molecule-1 (PECAM-1) localization were studied. For the first time, a flow facility was fully quantified for the uniformity of flow over ECs and for WSS determination (as opposed to relying on analytical equations). The SI and angle of orientation were found to be the most flow-sensitive morphometric parameters. A two-dimensional fast Fourier transform (2D FFT) based image processing technique was applied to analyze the F-actin directionality, and an alignment index (AI) was defined accordingly. Also, a significant peripheral loss of PECAM-1 in ECs subjected to atheroprone cases (LSL and NZMSL) with a high cell surface/cytoplasm stain of this protein is reported, which may shed light on of the mechanosensory role of PECAM-1 in mechanotransduction.

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Figures

Grahic Jump Location
Fig. 1

Illustration of the experimentally quantified WSS associated with the four different flow regimes studied (τw and t* representing the WSS and the time normalized by the pulse period for pulsatile cases, respectively): (a) LSL with the WSS of 1.13±0.10 dyn/cm2, (b) MSL with the WSS of 11.5±0.9 dyn/cm2, (c) NZMSL with the minimum, maximum, and mean WSS of −1.28, 2.02, and 0.25 dyn/cm2, and (d) LCRD with the minimum, maximum, and mean WSS of 3.32, 6.02, and 4.82 dyn/cm2. Note that the WSS is measured at three locations C, D, and F within the flow chamber for each flow case. A detailed discussion on the WSS quantification is reported in Ref. [33].

Grahic Jump Location
Fig. 2

Illustration of the method for determining the F-actin filament directionality using 2D FFT for the cells in the static control: (a) A 160 × 160 μm2 image cut-out of F-actin filaments (red) was taken from an image; (b) the image was converted into an 8-bit grayscale image; (c) then, it was transformed to the frequency domain applying the 2D FFT function, and the resulting image was rotated by 90 deg; (d) the image was then contrasted, and the pixel intensities were summed for every 10 deg peripheral band; and (e) histogram showing the relative pixel intensities (%) in 10 deg increments. In the present case, a somewhat uniform distribution of the relative intensities represents a random orientation of F-actin filaments for the static condition. The maximum values observed at angles 70–110 deg may also represent noise due to edge effects, as described by Dejana [35]. Scale bar = 40 μm.

Grahic Jump Location
Fig. 3

Bar graph illustrating the PAEC area (μm2) variation between the static and the flow treated conditions (LSL, MSL, NZMSL, and LCRD). A significant area increase was observed in LSL (b) flow conditions compared to the static control and MSL, NZMSL, and LCRD (a) flow cases. Note that the lower-case letters are to identify the experiment that is significantly different from the other groups. The experiments sharing the same letter were found not to be significantly different.

Grahic Jump Location
Fig. 4

Bar graph illustrating the PAEC perimeter (μm) variation between the static and the flow treated conditions (LSL, MSL, NZMSL, and LCRD). A significant increase was observed between the perimeter of the samples treated with the LSL and MSL (b) flow conditions when compared with the static control, NZMSL and LCRD (a) flow cases. Note that the lower-case letters are to identify the experiment that is significantly different from the other groups. The experiments sharing the same letter were found not to be significantly different.

Grahic Jump Location
Fig. 5

Histograms illustrating the distribution of the PAEC angle of orientation with the flow direction, θo (in 10 deg increments) for the static, LSL, MSL, NZMSL, and LCRD conditions

Grahic Jump Location
Fig. 6

The SI for PAEC in static, as well as the LSL, MSL, NZMSL, and LCRD flow conditions. The SI ranges between 0 and 1, the former describing a straight line, whereas the latter corresponds to a circle. A significant decrease was found for the LSL, NZMSL, LCRD (b) and MSL (c) cases experiments when compared with the static control (a). The SI for the MSL (c) flow was significantly smaller than for the other three (LSL, NZMSL, and LCRD) experiments (b). Note that the lower-case letters are to identify the experiment that is significantly different from the other groups. The experiments sharing the same letter were found not to be significantly different.

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Fig. 7

The SI for the static control and for the flow conditions reported in previous work [16,23,55]. The bars with the similar pattern represent the results of the same study.

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Fig. 8

The WSS remodels PAEC F-actin bundles and PECAM-1 localization. Immunofluorescence staining of F-actin bundles with Phalloidin (red), PECAM-1 with mouse anti-pig CD31 (green), and nuclei (blue) is presented. The images represent the static control ((a)–(d)) and LSL ((e)–(h)), MSL ((i)–(l)), NZMSL ((m)–(p)), and LCRD ((q)–(t)) flow conditions. Localization of PECAM-1 is shown in images B, F, J, N, and R. Nucleus staining is seen in images C, G, K, O, and S. Also, F-actin, PECAM-1, and nucleus merge images are presented in images D, H, L, P, and T.

Grahic Jump Location
Fig. 9

Representative histograms illustrating the alignment of the actin filaments using a 2D FFT method for PAECs subjected to LSL, MSL, NZMSL, and LCRD flows. The higher the peak in the histogram, the more aligned are the actin filaments in that 10 deg band. For comparison with the static control see Fig. 2(e).

Grahic Jump Location
Fig. 10

The effect of WSS on the AI for all cases. A significant increase was found between the static (a) and all the flow treated conditions ((b) and (c)). Also, the results showed a significant increase when the AI for the MSL and LCRD (c) flow treated ECs was compared with the LSL flow conditions (b) and a significant decrease when the AI for the NZMSL (b) flow condition was compared with the MSL flow condition (c). Note that the lower-case letters are to identify the experiment that is significantly different from the other groups. The experiments sharing the same letter were found not to be significantly different.

Grahic Jump Location
Fig. 11

Fluid-induced shear stress (WSS) modulates distribution of PECAM-1. The PRD was defined as a measure of peripheral PECAM-1. A significant decrease in the PRD was seen for the LSL and NZMSL (b) flow treated ECs when compared to the static control (a). These results also depict a significant increase in the PRD for the MSL and LCRD (a) flow treated ECs when compared to the LSL (b) flow condition. Similarly, a significant increase was observed in the results of the LCRD flow conditions when compared with the NZMSL flow case (b). Note that the lower-case letters are to identify the experiment that is significantly different from the other groups. The experiments sharing the same letter were found not to be significantly different.

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