Skip to main content
Log in

Effect of Spatial Heterogeneity and Colocalization of eNOS and Capacitative Calcium Entry Channels on Shear Stress-Induced NO Production by Endothelial Cells: A Modeling Approach

  • Published:
Cellular and Molecular Bioengineering Aims and scope Submit manuscript

Abstract

Colocalization of endothelial nitric oxide synthase (eNOS) and capacitative Ca2+ entry (CCE) channels in microdomains such as cavaeolae in endothelial cells (ECs) has been shown to significantly affect intracellular Ca2+ dynamics and NO production, but the effect has not been well quantified. We developed a two-dimensional continuum model of an EC integrating shear stress-mediated ATP production, intracellular Ca2+ mobilization, and eNOS activation to investigate the effects of spatial colocalization of plasma membrane eNOS and CCE channels on Ca2+ dynamics and NO production in response to flow-induced shear stress. Our model examines the hypothesis that subcellular colocalization of cellular components can be critical for optimal coupling of NO production to blood flow. Our simulations predict that heterogeneity of CCE can result in formation of microdomains with significantly higher Ca2+ compared to the average cytosolic Ca2+. Ca2+ buffers with lower or no mobility further enhanced Ca2+ gradients relative to mobile buffers. Colocalization of eNOS to CCE channels significantly increased NO production. Our results provide quantitative understanding for the role of spatial heterogeneity and the compartmentalization of signals in regulation of shear stress-induced NO production.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. A. Kapela, S. Nagaraja, Jaimit Parikh, and N. M. T. Modeling Ca2+ Signaling in the microcirculation: intercellular communication and vasoreactivity. Crit. Rev. Biomed. Eng. 39:435–460, 2011.

    Article  Google Scholar 

  2. Andrews, A. M., D. Jaron, D. G. Buerk, and K. A. Barbee. Shear stress-induced NO production is dependent on ATP autocrine signaling and capacitative calcium Entry. Cell. Mol. Bioeng. 7:510–520, 2014.

    Article  Google Scholar 

  3. Andrews, A. M., D. Jaron, D. G. Buerk, P. L. Kirby, and K. A. Barbee. Direct, real-time measurement of shear stress-induced nitric oxide produced from endothelial cells in vitro. Nitric Oxide 23:335–342, 2010.

    Article  Google Scholar 

  4. Balligand, J.-L., O. Feron, and C. Dessy. eNOS activation by physical forces: from short-term regulation of contraction to chronic remodeling of cardiovascular tissues. Physiol. Rev. 89:481–534, 2009.

    Article  Google Scholar 

  5. Béliveau, É., V. Lessard, and G. Guillemette. STIM1 positively regulates the Ca2+ release activity of the inositol 1,4,5-trisphosphate receptor in bovine aortic endothelial cells. PLoS ONE 9:e114718, 2014.

    Article  Google Scholar 

  6. Billaud, M., A. W. Lohman, S. R. Johnstone, L. A. Biwer, S. Mutchler, and B. E. Isakson. Regulation of cellular communication by signaling microdomains in the blood vessel wall. Pharmacol. Rev. 66:513–569, 2014.

    Article  Google Scholar 

  7. Bodin, P., D. Bailey, and G. Burnstock. Increased flow-induced ATP release from isolated vascular endothelial cells but not smooth muscle cells. Br. J. Pharmacol. 103:1203–1205, 1991.

    Article  Google Scholar 

  8. Busse, R., and A. Mülsch. Calcium-dependent nitric oxide synthesis in endothelial cytosol is mediated by calmodulin. FEBS Lett. 265:133–136, 1990.

    Article  Google Scholar 

  9. Cabral, P. D., N. J. Hong, and J. L. Garvin. ATP mediates flow-induced NO production in thick ascending limbs. Am. J. Physiol. Renal Physiol. 303:F194–F200, 2012.

    Article  Google Scholar 

  10. Chen, X., D. Jaron, K. A. Barbee, and D. G. Buerk. The influence of radial RBC distribution, blood velocity profiles, and glycocalyx on coupled NO/O2 transport. J. Appl. Physiol. 100:482–492, 2006.

    Article  Google Scholar 

  11. Comerford, A., M. J. Plank, and T. David. Endothelial nitric oxide synthase and calcium production in arterial geometries: an integrated fluid mechanics/cell model. J. Biomech. Eng. 130:011010, 2008.

    Article  Google Scholar 

  12. Dudzinski, D. M., J. Igarashi, D. Greif, and T. Michel. The regulation and pharmacology of endothelial nitric oxide synthase. Annu. Rev. Pharmacol. Toxicol. 46:235–276, 2006.

    Article  Google Scholar 

  13. Dupont, G., and A. Goldbeter. Properties of intracellular Ca2+ waves generated by a model based on Ca(2 +)-induced Ca2+ release. Biophys. J . 67:2191–2204, 1994.

    Article  Google Scholar 

  14. Francis, C. M., J. R. Waldrup, X. Qian, V. Solodushko, J. Meriwether, and M. S. Taylor. Functional tuning of intrinsic endothelial Ca2+ dynamics in swine coronary arteries. Circ. Res. 118:1078–1090, 2016.

    Article  Google Scholar 

  15. Fukumura, D., S. Kashiwagi, and R. K. Jain. The role of nitric oxide in tumour progression. Nat. Rev. Cancer 6:521–534, 2006.

    Article  Google Scholar 

  16. Fulton, D., R. Babbitt, S. Zoellner, J. Fontana, L. Acevedo, T. J. McCabe, Y. Iwakiri, and W. C. Sessa. Targeting of endothelial nitric-oxide synthase to the cytoplasmic face of the Golgi complex or plasma membrane regulates Akt- versus calcium-dependent mechanisms for nitric oxide release. J. Biol. Chem. 279:30349–30357, 2004.

    Article  Google Scholar 

  17. García-Cardeña, G., P. Oh, J. Liu, J. E. Schnitzer, and W. C. C. Sessa. Targeting of nitric oxide synthase to endothelial caveolae via palmitoylation. Proc. Natl. Acad. Sci. U.S.A. 10:6448–6453, 1996.

    Article  Google Scholar 

  18. Helmlinger, G., B. C. Berk, and R. M. Nerem. Pulsatile and steady flow-induced calcium oscillations in single cultured endothelial cells. J. Vasc. Res. 33:360–369, 1996.

    Article  Google Scholar 

  19. Hong, D. D. Jaron, D. G. Buerk, and K. a Barbee. Heterogeneous response of microvascular endothelial cells to shear stress. Am. J. Physiol. Heart Circ. Physiol. 290:H2498–H2508, 2006.

    Article  Google Scholar 

  20. Hong, D. D. Jaron, D. G. Buerk, and K. a Barbee. Transport-dependent calcium signaling in spatially segregated cellular caveolar domains. Am. J. Physiol. Cell Physiol. 294:C856–C866, 2008.

    Article  Google Scholar 

  21. Hu, X., C. Xiang, L. Cao, Z. Xu, and K. Qin. A mathematical model for ATP-mediated calcium dynamics in vascular endothelial cells induced by fluid shear stress. Appl. Math. Mech. 29:1291–1298, 2008.

    Article  MATH  Google Scholar 

  22. Ignarro, L. J., G. M. Buga, K. S. Wood, R. E. Byrns, and G. Chaudhuri. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A 84:9265–9269, 1987.

    Article  Google Scholar 

  23. Jin, Z.-G. Where is endothelial nitric oxide synthase more critical: plasma membrane or Golgi? Arterioscler. Thromb. Vasc. Biol. 26:959–961, 2006.

    Article  Google Scholar 

  24. Kirby, P. L., D. G. Buerk, J. Parikh, K. A. Barbee, and D. Jaron. Mathematical model for shear stress dependent NO and adenine nucleotide production from endothelial cells. Nitric Oxide 52:1–15, 2016.

    Article  Google Scholar 

  25. Ledoux, J., M. S. Taylor, A. D. Bonev, R. M. Hannah, V. Solodushko, B. Shui, Y. Tallini, M. I. Kotlikoff, and M. T. Nelson. Functional architecture of inositol 1,4,5-trisphosphate signaling in restricted spaces of myoendothelial projections. Proc. Natl. Acad. Sci. U.S.A. 105:9627–9632, 2008.

    Article  Google Scholar 

  26. Li, L.-F., C. Xiang, and K.-R. Qin. Modeling of TRPV-C1-mediated calcium signaling in vascular endothelial cells induced by fluid shear stress and ATP. Biomech. Model. Mechanobiol. 14:979–993, 2015.

    Article  Google Scholar 

  27. Lin, S., K. A. Fagan, K. X. Li, P. W. Shaul, D. M. F. Cooper, and D. M. Rodman. Sustained endothelial nitric-oxide synthase activation requires capacitative Ca2+ entry. J. Biol. Chem. 275:17979–17985, 2000.

    Article  Google Scholar 

  28. Means, S., A. J. Smith, J. Shepherd, J. Shadid, J. Fowler, R. J. H. Wojcikiewicz, T. Mazel, G. D. Smith, and B. S. Wilson. Reaction diffusion modeling of calcium dynamics with realistic ER geometry. Biophys. J . 91:537–557, 2006.

    Article  Google Scholar 

  29. Mo, M., S. G. Eskin, and W. P. Schilling. Flow-induced changes in Ca2+ signaling of vascular endothelial cells: effect of shear stress and ATP. Am. J. Physiol. 260:H1698–H1707, 1991.

    Google Scholar 

  30. Mount, P. F., B. E. Kemp, and D. A. Power. Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation. J. Mol. Cell. Cardiol. 42(2):271–279, 2007.

    Article  Google Scholar 

  31. Murthy, V. N., T. J. Sejnowski, and C. F. Stevens. Dynamics of dendritic calcium transients evoked by quantal release at excitatory hippocampal synapses. Proc. Natl. Acad. Sci. U.S.A. 97:901–906, 2000.

    Article  Google Scholar 

  32. Nakano, T., R. Tominaga, I. Nagano, H. Okabe, and H. Yasui. Pulsatile flow enhances endothelium-derived nitric oxide release in the peripheral vasculature. Am. J. Physiol. Heart Circ. Physiol. 278:H1098–H1104, 2000.

    Article  Google Scholar 

  33. Ogawa, K., and K. Taniguchi. Transport pathways for macromolecules in the aortic endothelium. II. The distribution analysis of plasmalemmal vesicles reconstructed by serial sections. Anat. Rec. 237:358–364, 1993.

    Article  Google Scholar 

  34. Palmer, R. M. J., A. Ferrige, and S. Moncada. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526, 1987.

    Article  Google Scholar 

  35. Parikh, J., A. Kapela, and N. M. Tsoukias. Stochastic model of endothelial TRPV4 calcium sparklets: effect of bursting and cooperativity on EDH. Biophys. J . 108:1566–1576, 2015.

    Article  Google Scholar 

  36. Pires, P. W., and S. Earley. No static at all. Circ. Res. 118:1042–1044, 2016.

    Article  Google Scholar 

  37. Plank, M. J., D. J. N. Wall, and T. David. Atherosclerosis and calcium signalling in endothelial cells. Prog. Biophys. Mol. Biol. 91:287–313, 2006.

    Article  Google Scholar 

  38. Qian, X., M. Francis, V. Solodushko, S. Earley, and M. S. Taylor. Recruitment of dynamic endothelial Ca2+ signals by the TRPA1 channel activator AITC in rat cerebral arteries. Microcirculation 20:138–148, 2013.

    Article  Google Scholar 

  39. Qin, K. R., C. Xiang, Z. Xu, L. L. Cao, S. S. Ge, and Z. L. Jiang. Dynamic modeling for shear stress induced ATP release from vascular endothelial cells. Biomech. Model. Mechanobiol. 7:345–353, 2008.

    Article  Google Scholar 

  40. Shen, J., F. W. Luscinskas, A. Connolly, C. F. Dewey, and M. A. Gimbrone. Fluid shear stress modulates cytosolic free calcium in vascular endothelial cells. Am. J. Physiol. 262:C384–C390, 1992.

    Article  Google Scholar 

  41. Shyy, J. Y. J., and S. Chien. Role of integrins in endothelial mechanosensing of shear stress. Circ. Res. 91(9):769–775, 2002.

    Article  Google Scholar 

  42. Simionescu, M., N. Simionescu, and G. E. Palade. Morphometric data on the endothelium of blood capillaries. J. Cell Biol. 60:128–152, 1974.

    Article  Google Scholar 

  43. Sonkusare, S. K., A. D. Bonev, J. Ledoux, W. Liedtke, M. I. Kotlikoff, T. J. Heppner, D. C. Hill-Eubanks, and M. T. Nelson. Elementary Ca2+ signals through endothelial TRPV4 channels regulate vascular function. Science 336(6081):597–601, 2012.

    Article  Google Scholar 

  44. Sriram, K., J. G. Laughlin, P. Rangamani, and D. M. Tartakovsky. Shear-induced nitric oxide production by endothelial Cells. Biophys. J . 111:208–221, 2016.

    Article  Google Scholar 

  45. Straub, A. C., A. W. Lohman, M. Billaud, S. R. Johnstone, S. T. Dwyer, M. Y. Lee, P. S. Bortz, A. K. Best, L. Columbus, B. Gaston, and B. E. Isakson. Endothelial cell expression of haemoglobin α regulates nitric oxide signalling. Nature 491:473–477, 2012.

    Article  Google Scholar 

  46. Tran, C. H. T., M. S. Taylor, F. Plane, S. Nagaraja, N. M. Tsoukias, V. Solodushko, E. J. Vigmond, T. Furstenhaupt, M. Brigdan, and D. G. Welsh. Endothelial Ca2+ wavelets and the induction of myoendothelial feedback. AJP Cell Physiol. 302:C1226–C1242, 2012.

    Article  Google Scholar 

  47. Tran, J., A. Magenau, M. Rodriguez, C. Rentero, T. Royo, C. Enrich, S. R. Thomas, T. Grewal, and K. Gaus. Activation of endothelial nitric oxide (eNOS) occurs through different membrane domains in endothelial cells. PLoS ONE 11:e0151556, 2016.

    Article  Google Scholar 

  48. Tsoukias, N. M. Calcium dynamics and signaling in vascular regulation: computational models. Wiley Interdiscip. Rev. Syst. Biol. Med. 3:93–106, 2011.

    Article  Google Scholar 

  49. Tykocki, N. R., and M. T. Nelson. Location, location, location: juxtaposed calcium-signaling microdomains as a novel model of the vascular smooth muscle myogenic response. J. Gen. Physiol. 146:129–132, 2015.

    Article  Google Scholar 

  50. Uhlmann, S., U. Friedrichs, W. Eichler, S. Hoffmann, and P. Wiedemann. Direct measurement of VEGF-induced nitric oxide production by choroidal endothelial cells. Microvasc. Res. 62:179–189, 2001.

    Article  Google Scholar 

  51. Wiesner, T. F., B. C. Berk, and R. M. Nerem. A mathematical model of cytosolic calcium dynamics in human umbilical vein endothelial cells. Am. J. Physiol. 270:C1556–C1569, 1996.

    Article  Google Scholar 

  52. Yamamoto, K., K. Furuya, M. Nakamura, E. Kobatake, M. Sokabe, and J. Ando. Visualization of flow-induced ATP release and triggering of Ca2+ waves at caveolae in vascular endothelial cells. J. Cell Sci. 124:3477–3483, 2011.

    Article  Google Scholar 

  53. Yamamoto, K., R. Korenaga, A. Kamiya, Z. Qi, M. Sokabe, and J. Ando. P2X(4) receptors mediate ATP-induced calcium influx in human vascular endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 279:H285–H292, 2000.

    Article  Google Scholar 

  54. Yamamoto, K., T. Sokabe, N. Ohura, H. Nakatsuka, A. Kamiya, and J. Ando. Endogenously released ATP mediates shear stress-induced Ca2+ influx into pulmonary artery endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 285:H793–H803, 2003.

    Article  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Heart, Lung and Blood Institute Grant U01HL116256.

Disclosures

Kenneth Barbee, Jaimit Parikh, Yien Liu, Donald Buerk, and Dov Jaron declare that they have no conflicts of interest.

Ethical standards

No human or animal studies were carried out by the authors for this article.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Dov Jaron.

Additional information

Associate Editor Aleksander S. Popel oversaw the review of this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Barbee, K.A., Parikh, J.B., Liu, Y. et al. Effect of Spatial Heterogeneity and Colocalization of eNOS and Capacitative Calcium Entry Channels on Shear Stress-Induced NO Production by Endothelial Cells: A Modeling Approach. Cel. Mol. Bioeng. 11, 143–155 (2018). https://doi.org/10.1007/s12195-018-0520-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12195-018-0520-4

Keywords

Navigation