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The Effects of Combined Cyclic Stretch and Pressure on the Aortic Valve Interstitial Cell Phenotype

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Abstract

Aortic valve interstitial cells (VIC) can exhibit phenotypic characteristics of fibroblasts, myofibroblasts, and smooth muscle cells. Others have proposed that valve cells become activated and exhibit myofibroblast or fibroblast characteristics during disease initiation and progression; however, the cues that modulate this phenotypic change remain unclear. We hypothesize that the mechanical forces experienced by the valve play a role in regulating the native phenotype of the valve and that altered mechanical forces result in an activated phenotype. Using a novel ex vivo cyclic stretch and pressure bioreactor, we subjected porcine aortic valve (AV) leaflets to combinations of normal and pathological stretch and pressure magnitudes. The myofibroblast markers α-SMA and Vimentin, along with the smooth muscle markers Calponin and Caldesmon, were analyzed using immunohistochemistry and immunoblotting. Tissue structure was analyzed using Movat’s pentachrome staining. We report that pathological stretch and pressure inhibited the contractile and possibly myofibroblast phenotypes as indicated by downregulation of the proteins α-SMA, Vimentin, and Calponin. In particular, Calponin downregulation implies depolymerization of actin filaments and possible conversion to a more synthetic (non-contractile) phenotype. This agreed well with the increase in spongiosa and fibrosa thickness observed under elevated pressure and stretch that are typically indicative of increased matrix synthesis. Our study therefore demonstrates how cyclic stretch and pressure may possibly act together to modulate the AVIC phenotype.

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References

  1. Balachandran, K., et al. An ex vivo study of the biological properties of porcine aortic valves in response to circumferential cyclic stretch. Ann. Biomed. Eng. 34(11):1655–1665, 2006.

    Article  PubMed  Google Scholar 

  2. Balachandran, K., et al. Elevated cyclic stretch alters matrix remodeling in aortic valve cusps—implications for degenerative aortic valve disease? Am. J. Physiol. Heart Circ. Physiol. 296(3):H756–H764, 2009.

    Article  PubMed  CAS  Google Scholar 

  3. Balachandran, K., et al. Elevated cyclic stretch induces aortic valve calcification in a bone morphogenic protein-dependent manner. Am. J. Pathol. 177(1):49–57, 2010.

    Article  PubMed  CAS  Google Scholar 

  4. Chester, A. H., and P. M. Taylor. Molecular and functional characteristics of heart-valve interstitial cells. Philos. Trans. R. Soc. Lond. B Biol. Sci. 362(1484):1437–1443, 2007.

    Article  PubMed  CAS  Google Scholar 

  5. Della Rocca, F., et al. Cell composition of the human pulmonary valve: a comparative study with the aortic valve-the VESALIO* project. Ann. Thorac. Surg. 70(5):1594–1600, 2000.

    Article  PubMed  CAS  Google Scholar 

  6. Desmouliere, A., et al. Apoptosis during wound healing, fibrocontractive diseases and vascular wall injury. Int. J. Biochem. Cell Biol. 29(1):19–30, 1997.

    Article  PubMed  CAS  Google Scholar 

  7. El-Mezgueldi, M. Calponin. Int. J. Biochem. Cell Biol. 28(11):1185–1189, 1996.

    Article  PubMed  CAS  Google Scholar 

  8. Franke, W. W., et al. Intermediate sized filaments of human endothelial cells. J. Cell Biol. 81(3):570–580, 1979.

    Article  PubMed  CAS  Google Scholar 

  9. Galqzkiewicz, B., et al. Polymerization of G-actin by caldesmon. FEBS Lett. 184(1):144–149, 1985.

    Article  Google Scholar 

  10. Hossain, M. M., et al. h2-Calponin is regulated by mechanical tension and modifies the function of actin cytoskeleton. J. Biol. Chem. 280(51):42442–42453, 2005.

    Article  PubMed  CAS  Google Scholar 

  11. Ingber, D. Mechanobiology and diseases of mechanotransduction. Ann. Med. 35(8):564–577, 2003.

    Article  PubMed  Google Scholar 

  12. Jian, B., et al. Progression of aortic valve stenosis: TGF-beta1 is present in calcified aortic valve cusps and promotes aortic valve interstitial cell calcification via apoptosis. Ann. Thorac. Surg. 75(2):457–465, 2003; (discussion 465–466).

    Article  PubMed  Google Scholar 

  13. Kake, T., et al. Calponin induces actin polymerization at low ionic strength and inhibits depolymerization of actin filaments. Biochem J 312:587–592, 1995.

    PubMed  CAS  Google Scholar 

  14. Konduri, S., et al. Normal physiological conditions maintain the biological characteristics of porcine aortic heart valves: an ex vivo organ culture study. Ann. Biomed. Eng. 33(9):1158–1166, 2005.

    Article  PubMed  Google Scholar 

  15. Liu, A. C., V. R. Joag, and A. I. Gotlieb. The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology. Am. J. Pathol. 171(5):1407–1418, 2007.

    Article  PubMed  CAS  Google Scholar 

  16. Marston, S. B., and C. S. Redwood. The molecular anatomy of caldesmon. Biochem. J. 279(1):1–16, 1991.

    PubMed  CAS  Google Scholar 

  17. Mehta, D., and S. J. Gunst. Actin polymerization stimulated by contractile activation regulates force development in canine tracheal smooth muscle. J. Physiol. Lond. 519(3):829–840, 1999.

    Article  PubMed  CAS  Google Scholar 

  18. Merryman, W. D., et al. Synergistic effects of cyclic tension and transforming growth factor-beta1 on the aortic valve myofibroblast. Cardiovasc. Pathol. 16(5):268–276, 2007.

    Article  PubMed  CAS  Google Scholar 

  19. Mohler, III, E. R. Mechanisms of aortic valve calcification. Am. J. Cardiol. 94(11):1396–1402, 2004.

    Article  PubMed  Google Scholar 

  20. North, A. J., et al. Calponin is localised in both the contractile apparatus and the cytoskeleton of smooth muscle cells. J. Cell Sci. 107(3):437–444, 1994.

    PubMed  CAS  Google Scholar 

  21. Philippe, S., et al. Design of an ex vivo culture system to investigate the effects of shear stress on cardiovascular tissue. J. Biomech. Eng. 130(3):035001, 2008.

    Article  Google Scholar 

  22. Rabkin, S. W. The association of hypertension and aortic valve sclerosis. Blood Press. 14(5):264–272, 2005.

    Article  PubMed  Google Scholar 

  23. Rabkin, E., et al. Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves. Circulation 104(21):2525–2532, 2001.

    Article  PubMed  CAS  Google Scholar 

  24. Rabkin-Aikawa, E., et al. Dynamic and reversible changes of interstitial cell phenotype during remodeling of cardiac valves. J. Heart Valve Dis. 13(5):841–847, 2004.

    PubMed  Google Scholar 

  25. Schneider, P. J., and J. D. Deck. Tissue and cell renewal in the natural aortic valve of rats: an autoradiographic study. Cardiovasc. Res. 15(4):181–189, 1981.

    Article  PubMed  CAS  Google Scholar 

  26. Schnittler, H. J., T. Schmandra, and D. Drenckhahn. Correlation of endothelial vimentin content with hemodynamic parameters. Histochem. Cell Biol. 110(2):161–167, 1998.

    Article  PubMed  CAS  Google Scholar 

  27. Sucosky, P., et al. Altered shear stress stimulates upregulation of endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-beta1-dependent pathway. Arterioscler. Thromb. Vasc. Biol. 29(2):254–260, 2009.

    Article  PubMed  CAS  Google Scholar 

  28. Taylor, P. M., et al. The cardiac valve interstitial cell. Int. J. Biochem. Cell Biol. 35(2):113–118, 2003.

    Article  PubMed  CAS  Google Scholar 

  29. Wang, N., and D. Stamenovic. Mechanics of vimentin intermediate filaments. J. Muscle Res. Cell Motil. 23(5):535–540, 2002.

    Article  PubMed  Google Scholar 

  30. Xing, Y., et al. Effects of constant static pressure on the biological properties of porcine aortic valve leaflets. Ann. Biomed. Eng. 32(4):555–562, 2004.

    Article  PubMed  Google Scholar 

  31. Xing, Y., et al. Cyclic pressure affects the biological properties of porcine aortic valve leaflets in a magnitude and frequency dependent manner. Ann. Biomed. Eng. 32(11):1461–1470, 2004.

    Article  PubMed  Google Scholar 

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Acknowledgments

National Science Foundation through the Engineering Research Center program at Georgia Tech/Emory Center for the Engineering of Living Tissues under award EEC-9731643. Holifield Farms for providing porcine hearts for the research. Patrick Thayer was supported by the President’s Undergraduate Research Award (PURA).

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Authors and Affiliations

  1. W.H. Coulter School of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA

    Patrick Thayer, Kartik Balachandran, Choon Hwai Yap, Sivakkumar Arjunon & Ajit P. Yoganathan

  2. School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA

    Swetha Rathan

  3. Department of Cardiology, Emory University, Atlanta, GA, USA

    Hanjoong Jo

Authors
  1. Patrick Thayer
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  2. Kartik Balachandran
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  3. Swetha Rathan
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  4. Choon Hwai Yap
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  5. Sivakkumar Arjunon
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  6. Hanjoong Jo
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  7. Ajit P. Yoganathan
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Correspondence to Ajit P. Yoganathan.

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Associate Editor Jane Grande-Allen oversaw the review of this article.

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Thayer, P., Balachandran, K., Rathan, S. et al. The Effects of Combined Cyclic Stretch and Pressure on the Aortic Valve Interstitial Cell Phenotype. Ann Biomed Eng 39, 1654–1667 (2011). https://doi.org/10.1007/s10439-011-0273-x

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  • DOI: https://doi.org/10.1007/s10439-011-0273-x

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