Annals of Biomedical Engineering

, Volume 31, Issue 2, pp 163–170

Chronic Pulsatile Shear Stress Alters Insulin-Like Growth Factor-I (IGF-I) Binding Protein Release In Vitro

  • Selim Elhadj
  • R. Michael Akers
  • Kimberly Forsten-Williams


Insulin-like growth factor-I (IGF-I) is a potent smooth muscle cell mitogen indicated to have a role in vascular disease. IGF-I stimulates proliferation via receptor activation but its activity is mediated by IGF binding proteins (IGFBPs). Since hemodynamics have been linked to vascular proliferative disorders, we studied how pulsatile low (5±2 dynes/cm2) and high (23±8 dynes/cm2) shear stresses impacted IGFBP metabolism in bovine aortic endothelial cells using the Cellmax capillary system. We modeled the pulsatile flow in our system using the Womersley model for flow inside a rigid tube and harmonic analysis revealed that the flow was sinusoidal with a frequency of ∼0.3 Hz for both shear stress treatments. Laminar flow was confirmed and the phase lag between the pressure and the flow found to be insignificant. Thus, our study provides a necessary characterization of this in vitro system as well as an investigation into how shear impacts the IGF axis. We found a significant difference in IGFBP distribution between treatments and, given that IGFBPs regulate IGF-I activity and that IGF-I-independent activities have been suggested for IGFBP-3, suggest that shear stress may indirectly regulate IGF-I activity, and, by extension, the effect of IGF-I on vascular pathologies. © 2003 Biomedical Engineering Society.

PAC2003: 8719Uv, 8715La, 8719Rr, 8714Ee, 8716Dg

Bovine aortic endothelial cells Vascular Model Growth factor IGFBP-3 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Arnqvist, H. J., K. E. Bornfeldt, Y. Chen, and T. Lindstrom. The insulin-like growth factor system in vascular smooth muscle: Interaction with insulin and growth factors. Metabolism44:58–66, 1995.Google Scholar
  2. 2.
    Bayes-Genis, A., C. A. Conover, and R. S. Schwartz. The insulin-like growth factor axis: A review of atherosclerosis and restenosis. Circ. Res.86:125–130, 2000.Google Scholar
  3. 3.
    Bornfeldt, K. E., E. W. Raines, T. Nakano, L. M. Graves, E. G. Krebs, and R. Ross. Insulin-like growth factor-I and platelet-derived growth factor-BB induce directed migration of human arterial smooth muscle cells via signaling pathways that are distinct from those of proliferation. J. Clin. Invest.93:1266–1274, 1994.Google Scholar
  4. 4.
    Breier, B. H., B. W. Gallaher, and P. D. Gluckman. Radioimmunoassay for insulin-like growth factor I: Solutions to some potential problems and pitfalls. J. Endocrinol.128:347–357, 1991.Google Scholar
  5. 5.
    Brown, T. D.Techniques for mechanical stimulation of cells A review. J. Biomech.33:3–14, 2000.Google Scholar
  6. 6.
    Buchanan, Jr., J. R., C. Kleinstreuer, G. A. Truskey, and M. Lei. Relation between nonuniform hemodynamics and sites of altered permeability and lesion growth at the rabbit aorto-celiac junction. Atherosclerosis (Berlin)143:27–40, 1999Google Scholar
  7. 7.
    Conklin, B. S., D. S. Zhong, W. Zhao, P. H. Lin, and C. Chen. Shear stress regulates occludin and VEGF expression in porcine arterial endothelial cells. J. Surg. Res.102:13–21, 2002.Google Scholar
  8. 8.
    Dahlfors, G., and H. J. Arnqvist. Vascular endothelial growth factor and transforming growth factor-beta1 regulate the expression of insulin-like growth factor-binding protein-3,-4, and-5 in large vessel endothelial cells. Endocrinology141:2062–2067, 2000.Google Scholar
  9. 9.
    Davies, P. F.Flow-mediated endothelial mechanotransduction. Physiol. Rev.75:519–560, 1995.Google Scholar
  10. 10.
    Delafontaine, P.Insulin-like growth factor I and its binding proteins in the cardiovascular system. Cardiovasc. Res.30:825–834, 1995.Google Scholar
  11. 11.
    Elhadj, S., S. A. Mousa, and K. Forsten-Williams. Chronic pulsatile shear stress impacts synthesis of proteoglycans by endothelial cells: Effect on platelet aggregation and coagulation. J. Cell. Biochem.86:239–250, 2002.Google Scholar
  12. 12.
    Eskin, S. G., and L. V. McIntire. Hemodynamic effects on atherosclerosis and thrombosis. Semin. Thromb. Hemost.14:170–174, 1988.Google Scholar
  13. 13.
    Ewel, C. H., and M. L. Foegh. Chronic graft rejection: Accelerated transplant arteriosclerosis. Immunol. Rev.134:21–31, 1993.Google Scholar
  14. 14.
    Farb, A., G. Sangiorgi, A. J. Carter, V. M. Walley, W. D. Edwards, R. S. Schwartz, and R. Virmani. Pathology of acute and chronic coronary stenting in humans. Circulation99:44–52, 1999.Google Scholar
  15. 15.
    Gosgnach, W., M. Challah, F. Coulet, J. B. Michel, and T. Battle. Shear stress induces angiotensin converting enzyme expression in cultured smooth muscle cells: Possible involvement of bFGF. Cardiovasc. Res.45:486–492, 2000.Google Scholar
  16. 16.
    Grant, M. B., T. J. Wargovich, D. M. Bush, D. W. Player, S. Caballero, M. Foegh, and P. E. Spoerri. Expression of IGF-1, IGF-1 receptor and TGF-beta following balloon angioplasty in atherosclerotic and normal rabbit iliac arteries: An immunocytochemical study. Regul. Pept.79:47–53, 1999.Google Scholar
  17. 17.
    Grant, M. B., T. J. Wargovich, E. A. Ellis, R. Tarnuzzer, S. Caballero, K. Estes, M. Rossing, P. E. Spoerri, and C. Pepine. Expression of IGF-I, IGF-I receptor and IGF binding proteins-1,-2,-3,-4 and-5 in human atherectomy specimens. Regul. Pept.67:137–144, 1996.Google Scholar
  18. 18.
    Greenwald, S. E., and C. L. Berry. Improving vascular grafts: The importance of mechanical and haemodynamic properties. J. Pathol.190:292–299, 2000.Google Scholar
  19. 19.
    Hale, J. F., D. A. McDonald, and J. R. Womersley. Velocity profiles of oscillating arterial flow, with some calculations of viscous drag and the Reynolds number. J. Physiol. (London)128:629–640, 1955.Google Scholar
  20. 20.
    Helmlinger, G., R. V. Geiger, S. Schreck, and R. M. Nerem. Effects of pulsatile flow on cultured vascular endothelial cell morphology. J. Biomech. Eng.113:123–131, 1991.Google Scholar
  21. 21.
    Hendrickson, R. J., S. S. Okada, P. A. Cahill, E. Yankah, J. V. Sitzmann, and E. M. Redmond. Ethanol inhibits basal and flow-induced vascular smooth muscle cell migrationJ. Surg. Res.84:64–70, 1999.Google Scholar
  22. 22.
    Hsiai, T. K., S. K. Cho, H. M. Honda, S. Hama, M. Navab, L. L. Demer, and C. M. Ho. Endothelial cell dynamics under pulsating flows: Significance of high versus low shear stress slew rates [(tau)/]. Ann. Biomed. Eng.30:646–656, 2002.Google Scholar
  23. 23.
    Hsieh, H. J., N. Q. Li, and J. A. Frangos. Pulsatile and steady flow induces c-fos expression in human endothelial cells. J. Cell Physiol.154:143–151, 1993.Google Scholar
  24. 24.
    Malek, A. M., S. L. Alper, and S. Izumo. Hemodynamic shear stress and its role in atherosclerosis. J. Am. Med. Assoc.282:2035–2042, 1999.Google Scholar
  25. 25.
    Motomura, N., H. Lou, H. Orskov, P. W. Ramwell, and M. L. Foegh. Exposure of vascular allografts to insulin-like growth factor-I (IGF-I) increases vascular expression of IGF-I ligand and receptor protein and accelerates arteriosclerosis in rats. Transplantation65:1024–1030, 1998.Google Scholar
  26. 26.
    Nakao, M., K. Ono, S. Fujisawa, and T. Iijima. Mechanical stress-induced Ca2+ entry and Cl-current in cultured human aortic endothelial cells. Am. J. Physiol.276:C238–249, 1999.Google Scholar
  27. 27.
    Papadaki, M., S. G. Eskin, J. Ruef, M. S. Runge, and L. V. McIntire. Fluid shear stress as a regulator of gene expression in vascular cells: Possible correlations with diabetic abnormalities. Diabetes Res. Clin. Pract.45:89–99, 1999.Google Scholar
  28. 28.
    Qiu, Y., and J. M. Tarbell. Interaction between wall shear stress and circumferential strain affects endothelial cell biochemical production. J. Vasc. Res.37:147–157, 2000.Google Scholar
  29. 29.
    Qiu, Y., and J. M. Tarbell. Numerical simulation of pulsatile flow in a compliant curved tube model of a coronary artery. J. Biomech. Eng.122:77–85, 2000.Google Scholar
  30. 30.
    Redmond, E. M., P. A. Cahill, and J. V. Sitzmann. Perfused transcapillary smooth muscle and endothelial cell co-culture—A novel model. In Vitro Cell Dev. Biol. Anim.31:601–609, 1995.Google Scholar
  31. 31.
    Redmond, E. M., J. P. Cullen, P. A. Cahill, J. V. Sitzmann, S. Stefansson, D. A. Lawrence, and S. S. Okada. Endothelial cells inhibit flow-induced smooth muscle cell migration: Role of plasminogen activator inhibitor-1. Circulation103:597–603, 2001.Google Scholar
  32. 32.
    Ross, R.Cellular and molecular studies of atherogenesis. Atherosclerosis (Berlin)131:S3–4, 1997.Google Scholar
  33. 33.
    Salacinski, H. J., S. Goldner, A. Giudiceandrea, G. Hamilton, A. M. Seifalian, A. Edwards, and R. J. Carson. The mechanical behavior of vascular grafts: A review. J. Biomater. Appl.15:241–278, 2001.Google Scholar
  34. 34.
    Schwartz, C. J., A. J. Valente, E. A. Sprague, J. L. Kelley, and R. M. Nerem. The pathogenesis of atherosclerosis: An overview. Clin. Cardiol.14:I1–16, 1991.Google Scholar
  35. 35.
    Weber, M. S., S. Purup, M. Vestergaard, R. M. Akers, and K. Sejrsen. Nutritional and somatotropin regulation of the mitogenic response of mammary cells to mammary tissue extracts. Domest. Anim. Endocrinol.18:159–164, 2000.Google Scholar
  36. 36.
    Wittstein, I. S., W. Qiu, R. C. Ziegelstein, Q. Hu, and D. A. Kass. Opposite effects of pressurized steady versus pulsatile perfusion on vascular endothelial cell cytosolic pH: Role of tyrosine kinase and mitogen-activated protein kinase signaling. Circ. Res.86:1230–1236, 2000.Google Scholar
  37. 37.
    Womersley, J. R.Method for the calculation of velocity, rate of flow and viscous drag in arteries when the pressure gradient is known. J. Physiol. (London)127:553–563, 1955.Google Scholar
  38. 38.
    Ziegler, T., K. Bouzourene, V. J. Harrison, H. R. Brunner, and D. Hayoz. Influence of oscillatory and unidirectional flow environments on the expression of endothelin and nitric oxide synthase in cultured endothelial cells. Arterioscler. Thromb. Vasc. Biol.18:686–692, 1998.-Google Scholar

Copyright information

© Biomedical Engineering Society 2003

Authors and Affiliations

  • Selim Elhadj
    • 1
  • R. Michael Akers
    • 2
  • Kimberly Forsten-Williams
    • 1
  1. 1.Department of Chemical EngineeringVirginia Polytechnic Institute and State UniversityBlacksburg
  2. 2.Department of Dairy ScienceVirginia Polytechnic Institute and State UniversityBlacksburg

Personalised recommendations