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TECHNICAL PAPERS

Selective Modulation of Endothelial Cell [Ca2+]i Response to Flow by the Onset Rate of Shear Stress

[+] Author and Article Information
Brett R. Blackman

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104

Lawrence E. Thibault, Kenneth A. Barbee

School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA 19104

J Biomech Eng 122(3), 274-282 (Feb 06, 2000) (9 pages) doi:10.1115/1.429660 History: Received October 21, 1999; Revised February 06, 2000
Copyright © 2000 by ASME
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Figures

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Peak calcium activation is dependent on shear stress and onset rate of shear stress (ORSS). Three-dimensional surface plots were fitted to the raw data in each treatment group using the least-squares curve-fitting algorithm. Contours of no treatment (A), EGTA (B), and neomycin pretreatment (C) show graphically the complex dependence of the Peak Calcium activation on ORSS and shear stress magnitude and the modulation of endothelial responsiveness due to interference with normal calcium signaling pathways. ORSS = shear stress/rise time; shear stress in dyn/cm2, peak calcium in nM.
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Controlled cell shearing device schematic
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Mechanical loading protocol. A trapezoidal loading function from 60 to 120 seconds was used. Shear stress was ramped up linearly in 0.01, 0.1, 1, or 10 seconds to a steady-state value of shear stress (1, 5, 10, or 30 dyn/cm2). The stress was maintained for 1 minute and decelerated to no flow in 1 second (decel time).
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Dependence of peak calcium on the magnitude of shear stress. Significant increases in peak [Ca2+]i were observed following the onset of flow compare to static controls (p<0.01). This response is clearly dependent on the magnitude of shear stress, showing a dose response from 5–30 dyn/cm2. Bars represent the mean ± standard deviations for each group (n=600 cells, m=15 experiments).
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Rise time modulation of peak calcium response. Markers represent the mean of each rise time group as follows: (⋄) 10 s; (□) 1 s; (▴) 100 ms; (○) 10 ms. An onset rate dependent response was observed for most shear stress levels (1, 5, 10 dyn/cm2), but not at the highest level (30 dyn/cm2). Statistical significance between rise time groups is outlined in Table 1 in the appendix (n=160 cells, m=4 exp or n=120 cells, m=3 exp (only 10 s condition)).
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Dependence of final calcium on the magnitude of shear stress. Markers represent the mean of each rise time group as follows: (⋄) 10 s; (□) 1 s; (▴) 100 ms; (○) 10 ms. A sustained post-stimulus level of calcium was dependent on high shear stress (10, 30 dyn/cm2) compared to lower stresses (1, 5 dyn/cm2). This final state of Ca2+ was also modulated by the onset rate of flow. Bars represent mean values of each MSS group (n=600 cells, m=15 experiments), and points represent the means for each rise time group (same number of groups as Fig. 4).
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Shear-stress-induced Ca2+i depends on extracellular [Ca2+] and IP3 mediated release. (A) Chelation of extracellular calcium (EGTA/Ca2+ free solution) resulted in a general modulation of the peak calcium response. The greatest reduction of peak Ca2+ occurred upon blocking the IP3-mediated Ca2+ release pathway (neomycin 5 mM), which was observed across all levels of shear stress. (B) Chelation of extracellular calcium (EGTA/Ca2+ free solution) abolished the sustained post-stimulus final Ca2+i response observed in the untreated experiments, but had only a modest effect with neomycin pretreatment. Bars represent mean ± standard deviations for each group (untreated, n=600 cells; EGTA, n=360 cells; neomycin, n=240 cells).

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