Biomechanics and Modeling in Mechanobiology

, Volume 18, Issue 1, pp 189–202 | Cite as

A microfluidic device with spatiotemporal wall shear stress and ATP signals to investigate the intracellular calcium dynamics in vascular endothelial cells

  • Zong-Zheng Chen
  • Wei-Mo Yuan
  • Cheng Xiang
  • De-Pei Zeng
  • Bo Liu
  • Kai-Rong QinEmail author
Original Paper


Intracellular calcium dynamics plays an important role in the regulation of vascular endothelial cellular functions. In order to probe the intracellular calcium dynamic response under synergistic effect of wall shear stress (WSS) and adenosine triphosphate (ATP) signals, a novel microfluidic device, which provides the adherent vascular endothelial cells (VECs) on the bottom of microchannel with WSS signal alone, ATP signal alone, and different combinations of WSS and ATP signals, is proposed based upon the principles of fluid mechanics and mass transfer. The spatiotemporal profiles of extracellular ATP signals from numerical simulation and experiment studies validate the implementation of our design. The intracellular calcium dynamics of VECs in response to either WSS signal or ATP signal alone, and different combinations of WSS and ATP signals have been investigated. It is found that the synergistic effect of the WSS and ATP signals plays a more significant role in the signal transduction of VECs rather than that from either WSS signal or ATP signal alone. In particular, under the combined stimuli of WSS and ATP signals with different amplitudes and frequencies, the amplitudes and frequencies of the intracellular Ca2+ dynamic signals are observed to be closely related to the amplitudes and frequencies of WSS or ATP signals.


Microfluidics Wall shear stress Adenosine triphosphate Spatiotemporal signal Intracellular calcium dynamics Vascular endothelial cells 



The project is, in part, supported by the National Natural Science Foundation of China (11672065, 31370948, 11172060).

Compliance with ethical standards

Conflicts of interest

The authors declare no conflicts of interest.

Supplementary material

10237_2018_1076_MOESM1_ESM.docx (464 kb)
Supplementary material 1 (DOCX 465 kb)


  1. Ando J, Kamiya A (1988) Cytoplasmic calcium response to fluid shear stress in cultured vascular endothelial cells. In Vitro Cell Dev 24:7–871Google Scholar
  2. Ando J, Ohtsuka A, Korenaga R, Kamiya A (1991) Effect of extracellular ATP level on flow-induced Ca++ response in cultured vascular endothelial cells. Biochem Biophys Res Commun 179:1192–1199CrossRefGoogle Scholar
  3. Berridge MJ, Lipp P, Bootman MD (2000) The versatility and universality of calcium signaling. Nat Rev Mol Cell Biol 1:11–21CrossRefGoogle Scholar
  4. Bibhas R, Tamal D, Debasish M, Maiti TK, Chakraborty S (2014) Oscillatory shear stress induced calcium flickers in osteoblast cells. Integr Biol 6:289–299CrossRefGoogle Scholar
  5. Chen ZZ, Gao ZM, Zeng DP, Liu B, Luan Y, Qin KR (2016) A Y-shaped microfluidic device to study the combined effect of wall shear stress and ATP signals on intracellular calcium dynamics in vascular endothelial cells. Micromachines 11:213CrossRefGoogle Scholar
  6. Chen ZZ, Yuan WM, Aziz AR, Gao ZM, Zeng DP, Liu B, Qin KR (2017) Transfer characteristics of dynamic biochemical signals in non-reversing pulsatile flows in a shallow Y-shaped microfluidic channel: signal filtering and nonlinear amplitude-frequency modulation. Appl Math Mech 10:1481–1496MathSciNetCrossRefGoogle Scholar
  7. Davies PF (1995) Flow-mediated endothelial mechanotransduction. Physiol Rev 75:519–560CrossRefGoogle Scholar
  8. Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI (1997) Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 386:855–858CrossRefGoogle Scholar
  9. Dolmetsch RE, Xu K, Lewis RS (1998) Calcium oscillations increase the efficiency and specificity of gene expression. Nature 392:933–936CrossRefGoogle Scholar
  10. Dull RO, Davies PF (1991) Flow modulation of agonist (ATP)-response (Ca2+) coupling in vascular endothelial cells. Am J Physiol 261:54–149Google Scholar
  11. Gosink EC, Forsberg EJ (1993) Effects of ATP and bradykinin on endothelial cell Ca2+ homeostasis and formation of cGMP and prostacyclin. Am J Physiol-Cell Physiol 265:C1620–C1629CrossRefGoogle Scholar
  12. Hallam TJ, Jacob R, Merritt JE (1989) Influx of bivalent cations can be independent of receptor stimulation in human endothelial cells. Biochem J 259:125–129CrossRefGoogle Scholar
  13. Helmlinger G, Berk BC, Nerem RM (1996) Pulsatile and steady flow-induced calcium oscillations in single cultured endothelial cells. J Vasc Res 33:360–369CrossRefGoogle Scholar
  14. James NL, Harrison DG, Nerem RM (1995) Effects of shear on endothelial cell calcium in the presence and absence of ATP. Federation Am Soc Exp Biol 9:968–973CrossRefGoogle Scholar
  15. Kim YT, Joshi SD, Messner WC, Leduc PR, Davidson LA (2011) Detection of dynamic spatiotemporal response to periodic chemical stimulation in a Xenopus Embryonic tissue. PLoS ONE 6:e14624CrossRefGoogle Scholar
  16. Kuczenski B, Ruder WC, Messner WC, Leduc PR (2009) Probing cellular dynamics with a chemical signal generator. PLoS ONE 4:e4847CrossRefGoogle Scholar
  17. Li YJ, Li YZ, Cao T, Qin KR (2013) Transport of dynamic biochemical signals in steady flow in a shallow Y-shaped microfluidic channel: effect of transverse diffusion and longitudinal dispersion. J Biomech Eng 135:121011–121019CrossRefGoogle Scholar
  18. Li LF, Xiang C, Qin KR (2015) Modeling of TRPV4-C1-mediated calcium signaling in vascular endothelial cells induced by fluid shear stress and ATP. Biomech Model Mech 14:1–15CrossRefGoogle Scholar
  19. Mo M, Eskin SG, Schilling WP (1991) Flow-induced changes in Ca2+ signaling of vascular endothelial cells: effect of shear stress and ATP. Am J Physiol 260:707–1698Google Scholar
  20. Qin KR, Xiang C, Xu Z, Cao LL, Ge SS, Jiang ZL (2008) Dynamic modeling for shear stress induced ATP release from vascular endothelial cells. Biomech Model Mechbiol 5:345–353CrossRefGoogle Scholar
  21. Qin KR, Xiang C, Ge SS (2010) Generation of dynamic biochemical signals with a tube mixer: effect of dispersion in an oscillatory flow. Heat Mass Transf 6:675–686CrossRefGoogle Scholar
  22. Shen J, Luscinskas FW, Gimbrone MA, Dewey CF (1994) Fluid flow modulates vascular endothelial cytosolic calcium responses to adenine nucleotides. Microcirculation 1:67–78CrossRefGoogle Scholar
  23. Shin H, Mahto SK, Kim JH, Rhee SW (2011) Exposure of BALB/3T3 fibroblast cells to temporal concentration profile of toxicant inside microfluidic device. Biochip J 5:214–219CrossRefGoogle Scholar
  24. Tanyeri M, Johnson EM, Schroeder CM (2010) Hydrodynamic trap for single particles and cells. Appl Phys Lett 22:224101CrossRefGoogle Scholar
  25. Yamada A, Katanosaka Y, Mohri S, Naruse K (2009) A rapid microfluidic switching system for analysis at the single cellular level. IEEE Trans Nanobiosci 8:306–311CrossRefGoogle Scholar
  26. Yamamoto K, Korenaga R, Kamiya A, Ando J (2000a) Fluid shear stress activates Ca2+ influx into human endothelial cells via P2X4 purinoceptors. Circ Res 87:385–391CrossRefGoogle Scholar
  27. Yamamoto K, Korenaga R, Kamiya A, Qi Z, Sokabe M, Ando J (2000b) P2X4 receptors mediate ATP-induced calcium influx in human vascular endothelial cells. Am J Physiolo-Heart Circ 279:H285–H292CrossRefGoogle Scholar
  28. Yamamoto K, Sokabe T, Ohura N, Nakatsuka H, Kamiya A, Ando J (2003) Endogenously released ATP mediates shear stress-induced Ca2+ influx into pulmonary artery endothelial cells. Am J Physiolo-Heart Circ 285:793–803CrossRefGoogle Scholar
  29. Yu M, Chen ZZ, Xiang C, Liu B, Xie HD, Qin KR (2016) Microfluidic-based single cell trapping using a combination of stagnation point flow and physical barrier. Acta Mech Sin 3:422–429CrossRefGoogle Scholar
  30. Zhang X, Grimley A, Bertram R, Roper MG (2010) Microfluidic system for generation of sinusoidal glucose waveforms for entrainment of islets of Langerhans. Anal Chem 82:6704–6711CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of Optoelectronic Engineering and Instrumentation Science and School of Biomedical EngineeringDalian University of TechnologyDalianChina
  2. 2.Department of Electrical and Computer EngineeringNational University of SingaporeSingaporeSingapore
  3. 3.First Affiliated Hospital of Shenzhen University (Shenzhen Second People’s Hospital)ShenzhenChina

Personalised recommendations