Skip to main content
SpringerLink
Log in

Endothelial Wound Recovery is Influenced by Treatment with Shear Stress, Wound Direction, and Substrate

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

Abstract

Proper and timely wound healing in the endothelium is vital for maintaining vascular homeostasis and preventing pathological conditions. The hemodynamic forces of the vasculature include shear stress and cyclic stretch. Here, we investigate the effects of shear stress on recovery of vertical or horizontal wounds that are perpendicular or parallel to flow, respectively under static or shearing condition. We further examined the effects of substrate difference on wound closure for cells on glass or silicone membrane using a modified flow chamber. Using bovine aortic endothelial cells, we analyzed wound area in scratch tests. We found that migration of cells into wound area was significantly enhanced on membrane substrate compared to glass under static condition, regardless of direction. However, continuously sheared wounds recovered differently between horizontal and vertical directions on glass, but better recovery was demonstrated in horizontal rather than vertical wounds on membrane. Here, we began to analyze the effects of flow induced shear stress and substrate difference on the direction of wound recovery in endothelial cells. We continue to investigate the effects of shear stress and substrate properties on the direction of endothelial wound recovery, in order to better understand how hemodynamic forces would affect endothelial wound healing.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Albuquerque, M. L., and A. S. Flozak. Patterns of living beta-actin movement in wounded human coronary artery endothelial cells exposed to shear stress. Exp. Cell Res. 270(2):223–234, 2001.

    Article  Google Scholar 

  2. Albuquerque, M. L., and A. S. Flozak. Wound closure in sheared endothelial cells is enhanced by modulation of vascular endothelial-cadherin expression and localization. Exp. Biol. Med. (Maywood) 227(11):1006–1016, 2002.

    Google Scholar 

  3. Albuquerque, M. L., C. M. Waters, U. Savla, H. W. Schnaper, and A. S. Flozak. Shear stress enhances human endothelial cell wound closure in vitro. Am. J. Physiol. Heart Circ. Physiol. 279(1):H293–H302, 2000.

    Google Scholar 

  4. Blake, G., and P. Ridker. Inflammatory bio-markers and cardiovascular risk prediction. J. Intern. Med. 252(4):283–294, 2002.

    Article  Google Scholar 

  5. Candiello, J., M. Balasubramani, E. M. Schreiber, G. J. Cole, U. Mayer, W. Halfter, and H. Lin. Biomechanical properties of native basement membranes. FEBS J. 274(11):2897–2908, 2007.

    Article  Google Scholar 

  6. Carmeliet, P., L. Moons, J. M. Stassen, M. De Mol, A. Bouche, J. J. van den Oord, M. Kockx, and D. Collen. Vascular wound healing and neointima formation induced by perivascular electric injury in mice. Am. J. Pathol. 150(2):761–776, 1997.

    Google Scholar 

  7. Chen, K. D., Y. S. Li, M. Kim, S. Li, S. Yuan, S. Chien, and J. Y. Shyy. Mechanotransduction in response to shear stress. Roles of receptor tyrosine kinases, integrins, and Shc. J. Biol. Chem. 274(26):18393–18400, 1999.

    Article  Google Scholar 

  8. Chien, S. Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell. Am. J. Physiol. Heart Circ. Physiol. 292(3):H1209–H1224, 2007.

    Article  Google Scholar 

  9. Chobanian, A. V., J. O. Menzoian, J. Shipman, K. Heath, and C. C. Haudenschild. Effects of endothelial denudation and cholesterol feeding on in vivo transport of albumin, glucose, and water across rabbit carotid artery. Circ. Res. 53(6):805–814, 1983.

    Article  Google Scholar 

  10. Davies, P. Flow-mediated endothelial mechanotransduction. Physiol. Rev. 75(3):519–560, 1995.

    Google Scholar 

  11. Dewey, Jr, C. F., S. R. Bussolari, M. A. Gimbrone, Jr, and P. F. Davies. The dynamic response of vascular endothelial cells to fluid shear stress. J. Biomech. Eng. 103(3):177–185, 1981.

    Article  Google Scholar 

  12. Diamond, S., J. Sharefkin, C. Dieffenbach, K. Frasier-Scott, L. McIntire, and S. Eskin. Tissue plasminogen activator messenger RNA levels increase in cultured human endothelial cells exposed to laminar shear stress. J. Cell. Physiol. 143(2):364–371, 1990.

    Article  Google Scholar 

  13. Dikeman, D. A., L. A. Rivera Rosado, T. A. Horn, C. S. Alves, K. Konstantopoulos, and J. T. Yang. alpha4 beta1-Integrin regulates directionally persistent cell migration in response to shear flow stimulation. Am. J. Physiol. Cell Physiol. 295(1):151–159, 2008.

    Article  Google Scholar 

  14. Discher, D. E., P. Janmey, and Y. L. Wang. Tissue cells feel and respond to the stiffness of their substrate. Science 310(5751):1139–1143, 2005.

    Article  Google Scholar 

  15. Ferns, G. A., A. L. Stewart-Lee, and E. E. Anggard. Arterial response to mechanical injury: balloon catheter de-endothelialization. Atherosclerosis 92(2–3):89–104, 1992.

    Article  Google Scholar 

  16. Flanagan, L. A., Y. E. Ju, B. Marg, M. Osterfield, and P. A. Janmey. Neurite branching on deformable substrates. NeuroReport 13(18):2411–2415, 2002.

    Article  Google Scholar 

  17. Frangos, J. A., L. V. McIntire, and S. G. Eskin. Shear stress induces stimulation of mammalian cell metabolism. Biotechnol. Bioeng. 32:1053–1060, 1988.

    Article  Google Scholar 

  18. Glagov, S., C. Zarins, D. Giddens, and D. Ku. Hemodynamics and atherosclerosis. Insights and perspectives gained from studies of human arteries. Arch. Pathol. Lab. Med. 112(10):1018–1031, 1988.

    Google Scholar 

  19. Gojova, A., and A. I. Barakat. Vascular endothelial wound closure under shear stress: role of membrane fluidity and flow-sensitive ion channels. J. Appl. Physiol. 98(6):2355–2362, 2005.

    Article  Google Scholar 

  20. Hsu, P. P., S. Li, Y. S. Li, S. Usami, A. Ratcliffe, X. Wang, and S. Chien. Effects of flow patterns on endothelial cell migration into a zone of mechanical denudation. Biochem. Biophys. Res. Commun. 285(3):751–759, 2001.

    Article  Google Scholar 

  21. Kadohama, T., K. Nishimura, Y. Hoshino, T. Sasajima, and B. E. Sumpio. Effects of different types of fluid shear stress on endothelial cell proliferation and survival. J. Cell. Physiol. 212(1):244–251, 2007.

    Article  Google Scholar 

  22. Ku, D., D. Giddens, C. Zarins, and S. Glagov. Pulsatile flow and atherosclerosis in the human carotid bifurcation. Positive correlation between plaque location and low oscillating shear stress. Arteriosclerosis 5(3):293–302, 1985.

    Article  Google Scholar 

  23. Kuchan, M., and J. Frangos. Role of calcium and calmodulin in flow-induced nitric oxide production in endothelial cells. Am. J. Physiol. 266(3 Pt 1):C628–C636, 1994.

    Google Scholar 

  24. Lammerding, J., L. G. Fong, J. Y. Ji, K. Reue, C. L. Stewart, S. G. Young, and R. T. Lee. Lamins A and C but not lamin B1 regulate nuclear mechanics. J. Biol. Chem. 281(35):25768–25780, 2006.

    Article  Google Scholar 

  25. Li, Y. S., J. H. Haga, and S. Chien. Molecular basis of the effects of shear stress on vascular endothelial cells. J. Biomech. 38(10):1949–1971, 2005.

    Article  Google Scholar 

  26. Lin, X., and B. P. Helmke. Micropatterned structural control suppresses mechanotaxis of endothelial cells. Biophys. J . 95(6):3066–3078, 2008.

    Article  Google Scholar 

  27. Liu, J. C., and D. A. Tirrell. Cell response to RGD density in cross-linked artificial extracellular matrix protein films. Biomacromolecules 9(11):2984–2988, 2008.

    Article  Google Scholar 

  28. Lo, C. M., H. B. Wang, M. Dembo, and Y. L. Wang. Cell movement is guided by the rigidity of the substrate. Biophys. J . 79(1):144–152, 2000.

    Article  Google Scholar 

  29. Malek, A., L. Jiang, I. Lee, W. Sessa, S. Izumo, and S. Alper. Induction of nitric oxide synthase mRNA by shear stress requires intracellular calcium and G-protein signals and is modulated by PI 3 kinase. Biochem. Biophys. Res. Commun. 254(1):231–242, 1999.

    Article  Google Scholar 

  30. Manivannan, S., J. P. Gleghorn, and C. M. Nelson. Engineered tissues to quantify collective cell migration during morphogenesis. Methods Mol. Biol. 886:173–182, 2012.

    Article  Google Scholar 

  31. Minami, Y., H. Kaneda, M. Inoue, M. Ikutomi, T. Morita, and T. Nakajima. Endothelial dysfunction following drug-eluting stent implantation: a systematic review of the literature. Int. J. Cardiol. 2012. doi:10.1016/j.ijcard.2012.03.084.

  32. Moretti, M., A. Prina-Mello, A. J. Reid, V. Barron, and P. J. Prendergast. Endothelial cell alignment on cyclically-stretched silicone surfaces. J. Mater. Sci. Mater. Med. 15(10):1159–1164, 2004.

    Article  Google Scholar 

  33. Peyton, S. R., and A. J. Putnam. Extracellular matrix rigidity governs smooth muscle cell motility in a biphasic fashion. J. Cell. Physiol. 204(1):198–209, 2005.

    Article  Google Scholar 

  34. Picon, P. D., S. C. Goncalves, M. V. Wainstein, A. F. Costa, C. V. Mengarda, R. P. Machado, G. L. Berlim, M. Edelweiss, M. I. Edelweiss, and J. P. Ribeiro. Atherosclerosis and acute arterial thrombosis in rabbits: a model using balloon desendothelization without dietary intervention. Braz. J. Med. Biol. Res. 30(3):415–417, 1997.

    Article  Google Scholar 

  35. Reinhart-King, C. A. Endothelial cell adhesion and migration. Methods Enzymol. 443:45–64, 2008.

    Article  Google Scholar 

  36. Riley, W. A., R. W. Barnes, G. W. Evans, and G. L. Burke. Ultrasonic measurement of the elastic modulus of the common carotid artery. The Atherosclerosis Risk in Communities (ARIC) Study. Stroke 23(7):952–956, 1992.

    Article  Google Scholar 

  37. Simmers, M. B., A. W. Pryor, and B. R. Blackman. Arterial shear stress regulates endothelial cell-directed migration, polarity, and morphology in confluent monolayers. Am. J. Physiol. Heart Circ. Physiol. 293(3):H1937–H1946, 2007.

    Article  Google Scholar 

  38. Takada, Y., E. Murphy, P. Pil, C. Chen, M. H. Ginsberg, and M. E. Hemler. Molecular cloning and expression of the cDNA for alpha 3 subunit of human alpha 3 beta 1 (VLA-3), an integrin receptor for fibronectin, laminin, and collagen. J. Cell Biol. 115(1):257–266, 1991.

    Article  Google Scholar 

  39. Teichert, A. M., J. A. Scott, G. B. Robb, Y. Q. Zhou, S. N. Zhu, M. Lem, A. Keightley, B. M. Steer, A. C. Schuh, S. L. Adamson, et al. Endothelial nitric oxide synthase gene expression during murine embryogenesis: commencement of expression in the embryo occurs with the establishment of a unidirectional circulatory system. Circ. Res. 103(1):24–33, 2008.

    Article  Google Scholar 

  40. Urbich, C., D. H. Walter, A. M. Zeiher, and S. Dimmeler. Laminar shear stress upregulates integrin expression: role in endothelial cell adhesion and apoptosis. Circ. Res. 87(8):683–689, 2000.

    Article  Google Scholar 

  41. Vyalov, S., B. L. Langille, and A. I. Gotlieb. Decreased blood flow rate disrupts endothelial repair in vivo. Am. J. Pathol. 149(6):2107–2118, 1996.

    Google Scholar 

  42. Wacker, B. K., S. K. Alford, E. A. Scott, M. Das Thakur, G. D. Longmore, and D. L. Elbert. Endothelial cell migration on RGD-peptide-containing PEG hydrogels in the presence of sphingosine 1-phosphate. Biophys. J. 94(1):273–285, 2008.

    Article  Google Scholar 

  43. Wang, Y., H. Miao, S. Li, K. D. Chen, Y. S. Li, S. Yuan, J. Y. Shyy, and S. Chien. Interplay between integrins and FLK-1 in shear stress-induced signaling. Am. J. Physiol. Cell Physiol. 283(5):C1540–C1547, 2002.

    Article  Google Scholar 

  44. Yeung, T., P. C. Georges, L. A. Flanagan, B. Marg, M. Ortiz, M. Funaki, N. Zahir, W. Ming, V. Weaver, and P. A. Janmey. Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion. Cell Motil. Cytoskeleton 60(1):24–34, 2005.

    Article  Google Scholar 

  45. Zarins, C., D. Giddens, B. Bharadvaj, V. Sottiurai, R. Mabon, and S. Glagov. Carotid bifurcation atherosclerosis. Quantitative correlation of plaque localization with flow velocity profiles and wall shear stress. Circ. Res. 53(4):502–514, 1983.

    Article  Google Scholar 

Download references

Acknowledgments

This study was funded partially by American Heart Association grant (09SDG2060548).

Conflict of interest

No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, 723 West Michigan Street, SL-220J, Indianapolis, IN, 46202, USA

    Mustafa F. Mavi & Julie Y. Ji

Authors
  1. Mustafa F. Mavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julie Y. Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Julie Y. Ji.

Additional information

Associate Editor Cheng Dong oversaw the review of this article.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mavi, M.F., Ji, J.Y. Endothelial Wound Recovery is Influenced by Treatment with Shear Stress, Wound Direction, and Substrate. Cel. Mol. Bioeng. 6, 310–325 (2013). https://doi.org/10.1007/s12195-013-0277-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12195-013-0277-8

Keywords

Search

Navigation