Skip to main content
SpringerLink
Log in

Normal Shear Stress and Vascular Smooth Muscle Cells Modulate Migration of Endothelial Cells Through Histone Deacetylase 6 Activation and Tubulin Acetylation

  • Published:
Annals of Biomedical Engineering Aims and scope Submit manuscript

Abstract

Endothelial cells (ECs) line the innermost of the blood vessel wall and are constantly subjected to shear stress imposed by blood flow. ECs were also influenced by the neighboring vascular smooth muscle cells (VSMCs). The bidirectional communication between ECs and VSMCs modulates vascular homeostasis. In this study, the involvement of histone deacetylase 6 (HDAC6) in modulating migration of ECs co-cultured with VSMCs by the normal level of laminar shear stress (NSS) was investigated. ECs was either cultured alone or co-cultured with VSMCs under static conditions or subjected to NSS of 15 dyne/cm2 by using a parallel-plate co-culture flow chamber system. It was demonstrated that both NSS and VSMCs could increase EC migration. The migration level of ECs co-cultured with VSMCs under NSS was not higher than that under the static condition. The process of EC migration regulated by VSMCs and NSS was associated with the increased expression of HDAC6 and low level of acetylated tubulin. The increase in HDAC6 expression was accompanied by a time-dependent decrease in the acetylation of tubulin in ECs co-cultured with VSMCs. Inhibition of the HDAC6 by siRNA or tributyrin, an inhibitor of HDACs, induced a parallel alteration in the migration and the acetylated tubulin of ECs co-cultured with VSMCs. It was observed by immunofluorescence staining that the acetylated tubulin was distributed mostly around the cell nucleus in ECs co-cultured with VSMCs. The results suggest that the NSS may display a protective function on the vascular homeostasis by modulating EC migration to a normal level in a VSMC-dependent manner. This modulation process involves the down-regulation of acetylated tubulin which results from increased HDAC6 activity in ECs.

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Babic, A. M., C. C. Chen, and L. F. Lau. Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin alpha(v)beta(3), promotes endothelial cell survival, and induces angiogenesis in vivo. Mol. Cell. Biol. 19:2958–2966, 1999.

    PubMed  CAS  Google Scholar 

  2. Badier-Commander, C., A. Couvelard, D. Henin, T. Verbeuren, J. B. Michel, and M. P. Jacob. Smooth muscle cell modulation and cytokine overproduction in varicose veins. An in situ study. J. Pathol. 193:398–407, 2001.

    Article  PubMed  CAS  Google Scholar 

  3. Barakat, A., and D. Lieu. Differential responsiveness of vascular endothelial cells to different types of fluid mechanical shear stress. Cell Biochem. Biophys. 38:323–343, 2003.

    Article  PubMed  CAS  Google Scholar 

  4. Barberis, L., C. Pasquali, D. Bertschy-Meier, A. Cuccurullo, C. Costa, C. Ambrogio, F. Vilbois, R. Chiarle, M. Wymann, F. Altruda, C. Rommel, and E. Hirsch. Leukocyte transmigration is modulated by chemokine-mediated PI3Kgamma-dependent phosphorylation of vimentin. Eur. J. Immunol. 39:1136–1146, 2009.

    Article  PubMed  CAS  Google Scholar 

  5. Bazzoni, G., P. Tonetti, L. Manzi, M. R. Cera, G. Balconi, and E. Dejana. Expression of junctional adhesion molecule—a prevents spontaneous and random motility. J. Cell Sci. 118:623–632, 2005.

    Article  PubMed  CAS  Google Scholar 

  6. Brevetti, G., V. Schiano, and M. Chiariello. Endothelial dysfunction: a key to the pathophysiology and natural history of peripheral arterial disease? Atherosclerosis 197:1–11, 2008.

    Article  PubMed  CAS  Google Scholar 

  7. Cambray-Deakin, M. A., and R. D. Burgoyne. Posttranslational modifications of alpha-tubulin: acetylated and detyrosinated forms in axons of rat cerebellum. J. Cell Biol. 104:1569–1574, 1987.

    Article  PubMed  CAS  Google Scholar 

  8. Chiu, J. J., L. J. Chen, S. F. Chang, P. L. Lee, C. I. Lee, M. C. Tsai, D. Y. Lee, H. P. Hsieh, S. Usami, and S. Chien. Shear stress inhibits smooth muscle cell-induced inflammatory gene expression in endothelial cells: role of NF-kappaB. Arterioscler. Thromb. Vasc. Biol. 25:963–969, 2005.

    Article  PubMed  CAS  Google Scholar 

  9. Cunningham, K. S., and A. I. Gotlieb. The role of shear stress in the pathogenesis of atherosclerosis. Lab. Invest. 85:9–23, 2005.

    Article  PubMed  CAS  Google Scholar 

  10. Danowski, B. A. Fibroblast contractility and actin organization are stimulated by microtubule inhibitors. J. Cell Sci. 93(Pt 2):255–266, 1989.

    PubMed  CAS  Google Scholar 

  11. Destaing, O., F. Saltel, B. Gilquin, A. Chabadel, S. Khochbin, S. Ory, and P. Jurdic. A novel Rho-mDia2-HDAC6 pathway controls podosome patterning through microtubule acetylation in osteoclasts. J. Cell Sci. 118:2901–2911, 2005.

    Article  PubMed  CAS  Google Scholar 

  12. Eiseler, T., H. Doppler, I. K. Yan, K. Kitatani, K. Mizuno, and P. Storz. Protein kinase D1 regulates cofilin-mediated F-actin reorganization and cell motility through slingshot. Nat. Cell Biol. 11:545–556, 2009.

    Article  PubMed  CAS  Google Scholar 

  13. Hu, Y. L., S. Li, H. Miao, T. C. Tsou, M. A. del Pozo, and S. Chien. Roles of microtubule dynamics and small GTPase Rac in endothelial cell migration and lamellipodium formation under flow. J. Vasc. Res. 39:465–476, 2002.

    Article  PubMed  CAS  Google Scholar 

  14. Hubbert, C., A. Guardiola, R. Shao, Y. Kawaguchi, A. Ito, A. Nixon, M. Yoshida, X. F. Wang, and T. P. Yao. HDAC6 is a microtubule-associated deacetylase. Nature 417:455–458, 2002.

    Article  PubMed  CAS  Google Scholar 

  15. Johnson, T. L., and R. M. Nerem. Endothelial connexin 37, connexin 40, and connexin 43 respond uniquely to substrate and shear stress. Endothelium 14:215–226, 2007.

    PubMed  CAS  Google Scholar 

  16. Khochbin, S., A. Verdel, C. Lemercier, and D. Seigneurin-Berny. Functional significance of histone deacetylase diversity. Curr. Opin. Genet. Dev. 11:162–166, 2001.

    Article  PubMed  CAS  Google Scholar 

  17. Kouchi, H., K. Nakamura, K. Fushimi, M. Sakaguchi, M. Miyazaki, T. Ohe, and M. Namba. Manumycin A, inhibitor of ras farnesyltransferase, inhibits proliferation and migration of rat vascular smooth muscle cells. Biochem. Biophys. Res. Commun. 264:915–920, 1999.

    Article  PubMed  CAS  Google Scholar 

  18. Kovacs, J. J., P. J. Murphy, S. Gaillard, X. Zhao, J. T. Wu, C. V. Nicchitta, M. Yoshida, D. O. Toft, W. B. Pratt, and T. P. Yao. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol. Cell 18:601–607, 2005.

    Article  PubMed  CAS  Google Scholar 

  19. Li, C., Y. Hu, G. Sturm, G. Wick, and Q. Xu. Ras/Rac-dependent activation of p38 mitogen-activated protein kinases in smooth muscle cells stimulated by cyclic strain stress. Arterioscler. Thromb. Vasc. Biol. 20:E1–E9, 2000.

    PubMed  CAS  Google Scholar 

  20. Otero, K., F. Martinez, A. Beltran, D. Gonzalez, B. Herrera, G. Quintero, R. Delgado, and A. Rojas. Albumin-derived advanced glycation end-products trigger the disruption of the vascular endothelial cadherin complex in cultured human and murine endothelial cells. Biochem. J. 359:567–574, 2001.

    Article  PubMed  CAS  Google Scholar 

  21. Palazzo, A., B. Ackerman, and G. G. Gundersen. Cell biology: tubulin acetylation and cell motility. Nature 421:230, 2003.

    Article  PubMed  CAS  Google Scholar 

  22. Qi, Y. X., M. J. Qu, D. K. Long, B. Liu, Q. P. Yao, S. Chien, and Z. L. Jiang. Rho-GDP dissociation inhibitor alpha downregulated by low shear stress promotes vascular smooth muscle cell migration and apoptosis: a proteomic analysis. Cardiovasc. Res. 80:114–122, 2008.

    Article  PubMed  CAS  Google Scholar 

  23. 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. Circulation 103:597–603, 2001.

    PubMed  CAS  Google Scholar 

  24. Ridley, A. J. Rho GTPases and cell migration. J. Cell Sci. 114:2713–2722, 2001.

    PubMed  CAS  Google Scholar 

  25. Rosenbaum, J. Cytoskeleton: functions for tubulin modifications at last. Curr. Biol. 10:R801–R803, 2000.

    Article  PubMed  CAS  Google Scholar 

  26. Saji, S., M. Kawakami, S. Hayashi, N. Yoshida, M. Hirose, S. Horiguchi, A. Itoh, N. Funata, S. L. Schreiber, M. Yoshida, and M. Toi. Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer. Oncogene 24:4531–4539, 2005.

    Article  PubMed  CAS  Google Scholar 

  27. Schroder, E. A., K. Tobita, J. P. Tinney, J. K. Foldes, and B. B. Keller. Microtubule involvement in the adaptation to altered mechanical load in developing chick myocardium. Circ. Res. 91:353–359, 2002.

    Article  PubMed  CAS  Google Scholar 

  28. 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:H1937–H1946, 2007.

    Article  PubMed  CAS  Google Scholar 

  29. Spagnoli, L. G., S. Villaschi, L. Neri, and G. Palmieri. Gap junctions in myo-endothelial bridges of rabbit carotid arteries. Experientia 38:124–125, 1982.

    Article  PubMed  CAS  Google Scholar 

  30. Tressel, S. L., R. P. Huang, N. Tomsen, and H. Jo. Laminar shear inhibits tubule formation and migration of endothelial cells by an angiopoietin-2 dependent mechanism. Arterioscler. Thromb. Vasc. Biol. 27:2150–2156, 2007.

    Article  PubMed  CAS  Google Scholar 

  31. Tsai, M. C., L. Chen, J. Zhou, Z. Tang, T. F. Hsu, Y. Wang, Y. T. Shih, H. H. Peng, N. Wang, Y. Guan, S. Chien, and J. J. Chiu. Shear stress induces synthetic-to-contractile phenotypic modulation in smooth muscle cells via peroxisome proliferator-activated receptor alpha/delta activations by prostacyclin released by sheared endothelial cells. Circ. Res. 105:471–480, 2009.

    Article  PubMed  CAS  Google Scholar 

  32. Urbich, C., E. Dernbach, A. Reissner, M. Vasa, A. M. Zeiher, and S. Dimmeler. Shear stress-induced endothelial cell migration involves integrin signaling via the fibronectin receptor subunits alpha(5) and beta(1). Arterioscler. Thromb. Vasc. Biol. 22:69–75, 2002.

    Article  PubMed  CAS  Google Scholar 

  33. Vinogradova, T., P. M. Miller, and I. Kaverina. Microtubule network asymmetry in motile cells: role of Golgi-derived array. Cell Cycle 8:2168–2174, 2009.

    PubMed  CAS  Google Scholar 

  34. Wang, H. Q., L. X. Huang, M. J. Qu, Z. Q. Yan, B. Liu, B. R. Shen, and Z. L. Jiang. Shear stress protects against endothelial regulation of vascular smooth muscle cell migration in a coculture system. Endothelium 13:171–180, 2006.

    Article  PubMed  CAS  Google Scholar 

  35. Williams, C., and T. M. Wick. Endothelial cell-smooth muscle cell co-culture in a perfusion bioreactor system. Ann. Biomed. Eng. 33:920–928, 2005.

    Article  PubMed  Google Scholar 

  36. Zhang, X., Z. Yuan, Y. Zhang, S. Yong, A. Salas-Burgos, J. Koomen, N. Olashaw, J. T. Parsons, X. J. Yang, S. R. Dent, T. P. Yao, W. S. Lane, and E. Seto. HDAC6 modulates cell motility by altering the acetylation level of cortactin. Mol. Cell 27:197–213, 2007.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This research was supported by grants from the National Natural Science Foundation of China, Nos. 10732070, 10772120 and 10572096.

Author information

Authors and Affiliations

  1. Institute of Mechanobiology & Medical Engineering, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, P.O. Box 888, 800 Dongchuan Road, Minhang, Shanghai, 200240, China

    Yan-Hua Wang, Zhi-Qiang Yan, Ying-Xin Qi, Bin-Bin Cheng, Xiao-Dong Wang, Dan Zhao, Bao-Rong Shen & Zong-Lai Jiang

  2. School of Life Sciences and Technology, Nanyang Normal University, Henan, China

    Yan-Hua Wang

Authors
  1. Yan-Hua Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhi-Qiang Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ying-Xin Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bin-Bin Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiao-Dong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bao-Rong Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zong-Lai Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zong-Lai Jiang.

Additional information

Associate Editor Larry V. McIntire oversaw the review of this article.

Yan-Hua Wang and Zhi-Qiang Yan contributed equally to this article.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, YH., Yan, ZQ., Qi, YX. et al. Normal Shear Stress and Vascular Smooth Muscle Cells Modulate Migration of Endothelial Cells Through Histone Deacetylase 6 Activation and Tubulin Acetylation. Ann Biomed Eng 38, 729–737 (2010). https://doi.org/10.1007/s10439-009-9896-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10439-009-9896-6

Keywords

Search

Navigation