Advertisement

The Role of Proteoglycans and Glycosaminoglycans in Heart Valve Biomechanics

  • Varun K. Krishnamurthy
  • K. Jane Grande-AllenEmail author
Chapter

Abstract

Proteoglycans (PGs) and glycosaminoglycans (GAGs) have long been recognized as constituents of heart valves but their precise functions have been mysterious and underrepresented. The heterogeneity, dynamic processing and viscoelastic nature of PGs and GAGs, and their ability to exist independently or in association with other extracellular matrix (ECM) components, contribute to the overall complexity of valve ECM (structure), and impact local tissue biomechanics (function). This chapter will discuss various approaches for elucidating the biomechanical properties of valvular PGs and GAGs, will relate valve tissue hemodynamic alterations and valve cell biomechanical stimuli to differences in PG/GAG expression (and misexpression), and will address directions for future studies.

Keywords

Aortic and mitral valves Cell and organ culture Bioreactor Animal models Valve disease Tissue engineering Bioprostheses 

Notes

Acknowledgements

The authors would like to thanks Dr. Jennifer Petsche Connell and Andy Zhang for assistance in the preparation of this chapter.

References

  1. 1.
    Latif N, Sarathchandra P, Taylor PM, Antoniw J, Yacoub MH. Localization and pattern of expression of extracellular matrix components in human heart valves. J Heart Valve Dis. 2005;14:218–27.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Sacks MS, David Merryman W, Schmidt DE. On the biomechanics of heart valve function. J Biomech. 2009;42:1804–24.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Gupta V, Barzilla JE, Mendez JS, Stephens EH, Lee EL, Collard CD, Laucirica R, Weigel PH, Grande-Allen KJ. Abundance and location of proteoglycans and hyaluronan within normal and myxomatous mitral valves. Cardiovasc Pathol. 2009;18:191–7.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Hinton RB Jr, Lincoln J, Deutsch GH, Osinska H, Manning PB, Benson DW, Yutzey KE. Extracellular matrix remodeling and organization in developing and diseased aortic valves. Circ Res. 2006;98:1431–8.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Lockhart M, Wirrig E, Phelps A, Wessels A. Extracellular matrix and heart development. Birth Defects Res A Clin Mol Teratol. 2011;91:535–50.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Taylor PM, Batten P, Brand NJ, Thomas PS, Yacoub MH. The cardiac valve interstitial cell. Int J Biochem Cell Biol. 2003;35:113–8.CrossRefGoogle Scholar
  7. 7.
    Iozzo RV, Goldoni S, Berendsen A, Young MF. Small leucine-rich proteoglycans. In: Mecham RP, editor. Extracellular matrix: an overview, biology of extracellular matrix. Berlin Heidelberg: Springer; 2011.Google Scholar
  8. 8.
    Wight TN, Toole BP, Hascall VC. Hyaluronan and the aggregating proteoglycans. In: Mecham RP, editor. Extracellular matrix: an overview, biology of extracellular matrix. Berlin Heidelberg: Springer; 2011.Google Scholar
  9. 9.
    Esko JD, Kimata K, Lindahl U. Proteoglycans and sulfated glycosaminoglycans. In: Varki A, Cummings RD, Esko JD, et al., editors. Essentials of glycobiology. 2nd ed. Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 2009.Google Scholar
  10. 10.
    Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden of valvular heart diseases: a population-based study. Lancet. 2006;368:1005–11.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Stephens EH, Chu CK, Grande-Allen KJ. Valve proteoglycan content and glycosaminoglycan fine structure are unique to microstructure, mechanical load and age: relevance to an age-specific tissue-engineered heart valve. Acta Biomater. 2008;4:1148–60.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Chang Y, Yanagishita M, Hascall VC, Wight TN. Proteoglycans synthesized by smooth muscle cells derived from monkey (Macaca nemestrina) aorta. J Biol Chem. 1983;258:5679–88.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Schonherr E, Jarvelainen HT, Sandell LJ, Wight TN. Effects of platelet-derived growth factor and transforming growth factor-beta 1 on the synthesis of a large versican-like chondroitin sulfate proteoglycan by arterial smooth muscle cells. J Biol Chem. 1991;266:17640–7.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Zimmermann DR, Ruoslahti E. Multiple domains of the large fibroblast proteoglycan, versican. EMBO J. 1989;8:2975–81.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Rabkin E, Aikawa M, Stone JR, Fukumoto Y, Libby P, Schoen FJ. Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves. Circulation. 2001;104:2525–32.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Grande-Allen KJ, Calabro A, Gupta V, Wight TN, Hascall VC, Vesely I. Glycosaminoglycans and proteoglycans in normal mitral valve leaflets and chordae: association with regions of tensile and compressive loading. Glycobiology. 2004;14:621–33.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Krishnamurthy VK, Godby RC, Liu GR, Smith JM, Hiratzka LF, Narmoneva DA, Hinton RB. Review of molecular and mechanical interactions in the aortic valve and aorta: implications for the shared pathogenesis of aortic valve disease and aortopathy. J Cardiovasc Transl Res. 2014;7:823–46.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Hinek A, Rabinovitch M. 67-kD elastin-binding protein is a protective “companion” of extracellular insoluble elastin and intracellular tropoelastin. J Cell Biol. 1994;126:563–74.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Wu YJ, La Pierre DP, Wu J, Yee AJ, Yang BB. The interaction of versican with its binding partners. Cell Res. 2005;15:483–94.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Krishnamurthy VK, Opoka AM, Kern CB, Guilak F, Narmoneva DA, Hinton RB. Maladaptive matrix remodeling and regional biomechanical dysfunction in a mouse model of aortic valve disease. Matrix Biol. 2012;31:197–205.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Tseng H, Grande-Allen KJ. Elastic fibers in the aortic valve spongiosa: a fresh perspective on its structure and role in overall tissue function. Acta Biomater. 2011;7:2101–8.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Reinboth B, Hanssen E, Cleary EG, Gibson MA. Molecular interactions of biglycan and decorin with elastic fiber components: biglycan forms a ternary complex with tropoelastin and microfibril-associated glycoprotein 1. J Biol Chem. 2002;277:3950–7.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Dupuis LE, Kern CB. Small leucine-rich proteoglycans exhibit unique spatiotemporal expression profiles during cardiac valve development. Dev Dyn. 2014;243:601–11.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Hwang JY, Johnson PY, Braun KR, Hinek A, Fischer JW, O'Brien KD, Starcher B, Clowes AW, Merrilees MJ, Wight TN. Retrovirally mediated overexpression of glycosaminoglycan-deficient biglycan in arterial smooth muscle cells induces tropoelastin synthesis and elastic fiber formation in vitro and in neointimae after vascular injury. Am J Pathol. 2008;173:1919–28.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Geng Y, McQuillan D, Roughley PJ. SLRP interaction can protect collagen fibrils from cleavage by collagenases. Matrix Biol. 2006;25:484–91.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Kalamajski S, Oldberg A. The role of small leucine-rich proteoglycans in collagen fibrillogenesis. Matrix Biol. 2010;29:248–53.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Redaelli A, Vesentini S, Soncini M, Vena P, Mantero S, Montevecchi FM. Possible role of decorin glycosaminoglycans in fibril to fibril force transfer in relative mature tendons--a computational study from molecular to microstructural level. J Biomech. 2003;36:1555–69.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Zhang G, Chen S, Goldoni S, Calder BW, Simpson HC, Owens RT, McQuillan DJ, Young MF, Iozzo RV, Birk DE. Genetic evidence for the coordinated regulation of collagen fibrillogenesis in the cornea by decorin and biglycan. J Biol Chem. 2009;284:8888–97.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Zhang G, Ezura Y, Chervoneva I, Robinson PS, Beason DP, Carine ET, Soslowsky LJ, Iozzo RV, Birk DE. Decorin regulates assembly of collagen fibrils and acquisition of biomechanical properties during tendon development. J Cell Biochem. 2006;98:1436–49.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Dupuis LE, Doucette L, Rice AK, Lancaster AE, Berger MG, Chakravarti S, Kern CB. Development of myotendinous-like junctions that anchor cardiac valves requires fibromodulin and lumican. Dev Dyn. 2016;245:1029–42.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Manji RA, Menkis AH, Ekser B, Cooper DK. Porcine bioprosthetic heart valves: the next generation. Am Heart J. 2012;164:177–85.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Schoen FJ. Evolving concepts of cardiac valve dynamics: the continuum of development, functional structure, pathobiology, and tissue engineering. Circulation. 2008;118:1864–80.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Siddiqui RF, Abraham JR, Butany J. Bioprosthetic heart valves: modes of failure. Histopathology. 2009;55:135–44.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Zilla P, Brink J, Human P, Bezuidenhout D. Prosthetic heart valves: catering for the few. Biomaterials. 2008;29:385–406.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Lovekamp JJ, Simionescu DT, Mercuri JJ, Zubiate B, Sacks MS, Vyavahare NR. Stability and function of glycosaminoglycans in porcine bioprosthetic heart valves. Biomaterials. 2006;27:1507–18.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Vyavahare N, Ogle M, Schoen FJ, Zand R, Gloeckner DC, Sacks M, Levy RJ. Mechanisms of bioprosthetic heart valve failure: fatigue causes collagen denaturation and glycosaminoglycan loss. J Biomed Mater Res. 1999;46:44–50.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Shah SR, Vyavahare NR. The effect of glycosaminoglycan stabilization on tissue buckling in bioprosthetic heart valves. Biomaterials. 2008;29:1645–53.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Simionescu DT, Lovekamp JJ, Vyavahare NR. Glycosaminoglycan-degrading enzymes in porcine aortic heart valves: implications for bioprosthetic heart valve degeneration. J Heart Valve Dis. 2003;12:217–25.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Grande-Allen KJ, Mako WJ, Calabro A, Shi Y, Ratliff NB, Vesely I. Loss of chondroitin 6-sulfate and hyaluronan from failed porcine bioprosthetic valves. J Biomed Mater Res A. 2003;65:251–9.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Friebe VM, Mikulis B, Kole S, Ruffing CS, Sacks MS, Vyavahare NR. Neomycin enhances extracellular matrix stability of glutaraldehyde crosslinked bioprosthetic heart valves. J Biomed Mater Res B Appl Biomater. 2011;99:217–29.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Tam H, Zhang W, Feaver KR, Parchment N, Sacks MS, Vyavahare N. A novel crosslinking method for improved tear resistance and biocompatibility of tissue based biomaterials. Biomaterials. 2015;66:83–91.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Tripi DR, Vyavahare NR. Neomycin and pentagalloyl glucose enhanced cross-linking for elastin and glycosaminoglycans preservation in bioprosthetic heart valves. J Biomater Appl. 2014;28:757–66.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Stella JA, Sacks MS. On the biaxial mechanical properties of the layers of the aortic valve leaflet. J Biomech Eng. 2007;129:757–66.CrossRefGoogle Scholar
  44. 44.
    Thornton GM, Frank CB, Shrive NG. Ligament creep behavior can be predicted from stress relaxation by incorporating fiber recruitment. J Rheol. 2001;45:493–507.CrossRefGoogle Scholar
  45. 45.
    Buchanan RM, Sacks MS. Interlayer micromechanics of the aortic heart valve leaflet. Biomech Model Mechanobiol. 2014;13:813–26.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Roccabianca S, Ateshian GA, Humphrey JD. Biomechanical roles of medial pooling of glycosaminoglycans in thoracic aortic dissection. Biomech Model Mechanobiol. 2014;13:13–25.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Schmidt MB, Mow VC, Chun LE, Eyre DR. Effects of proteoglycan extraction on the tensile behavior of articular cartilage. J Orthop Res. 1990;8:353–63.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Lincoln J, Lange AW, Yutzey KE. Hearts and bones: shared regulatory mechanisms in heart valve, cartilage, tendon, and bone development. Dev Biol. 2006;294:292–302.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Bhatia A, Vesely I. The effect of glycosaminoglycans and hydration on the viscoelastic properties of aortic valve cusps. Conf Proc IEEE Eng Med Biol Soc. 2005;3:2979–80.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Eckert CE, Fan R, Mikulis B, Barron M, Carruthers CA, Friebe VM, Vyavahare NR, Sacks MS. On the biomechanical role of glycosaminoglycans in the aortic heart valve leaflet. Acta Biomater. 2013;9:4653–60.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Borghi A, New SE, Chester AH, Taylor PM, Yacoub MH. Time-dependent mechanical properties of aortic valve cusps: effect of glycosaminoglycan depletion. Acta Biomater. 2013;9:4645–52.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Tseng H, Kim EJ, Connell PS, Ayoub S, Shah JV, Grande-Allen KJ. The tensile and viscoelastic properties of aortic valve leaflets treated with a hyaluronidase gradient. Cardiovasc. Eng Technol 2013;4(2):151–160.  https://doi.org/10.1007/s13239-013-0122-1.CrossRefGoogle Scholar
  53. 53.
    Talman EA, Boughner DR. Effect of altered hydration on the internal shear properties of porcine aortic valve cusps. Ann Thorac Surg. 2001;71:S375–8.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Xing Y, Warnock JN, He Z, Hilbert SL, Yoganathan AP. Cyclic pressure affects the biological properties of porcine aortic valve leaflets in a magnitude and frequency dependent manner. Ann Biomed Eng. 2004;32:1461–70.CrossRefGoogle Scholar
  55. 55.
    Merryman WD, Lukoff HD, Long RA, Engelmayr GC Jr, Hopkins RA, Sacks MS. Synergistic effects of cyclic tension and transforming growth factor-beta1 on the aortic valve myofibroblast. Cardiovasc Pathol. 2007;16:268–76.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Thayer P, Balachandran K, Rathan S, Yap CH, Arjunon S, Jo H, Yoganathan AP. The effects of combined cyclic stretch and pressure on the aortic valve interstitial cell phenotype. Ann Biomed Eng. 2011;39:1654–67.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Barzilla JE, McKenney AS, Cowan AE, Durst CA, Grande-Allen KJ. Design and validation of a novel splashing bioreactor system for use in mitral valve organ culture. Ann Biomed Eng. 2010;38:3280–94.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Balachandran K, Bakay MA, Connolly JM, Zhang X, Yoganathan AP, Levy RJ. Aortic valve cyclic stretch causes increased remodeling activity and enhanced serotonin receptor responsiveness. Ann Thorac Surg. 2011;92:147–53.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Lacerda CM, Kisiday J, Johnson B, Orton EC. Local serotonin mediates cyclic strain-induced phenotype transformation, matrix degradation, and glycosaminoglycan synthesis in cultured sheep mitral valves. Am J Physiol Heart Circ Physiol. 2012;302:H1983–90.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Connell PS, Azimuddin AF, Kim SE, Ramirez F, Jackson MS, Little SH, Grande-Allen KJ. Regurgitation hemodynamics alone cause mitral valve remodeling characteristic of clinical disease states in vitro. Ann Biomed Eng. 2016;44(4):954–67.  https://doi.org/10.1007/s10439-015-1398-0.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Sapp MC, Krishnamurthy VK, Puperi DS, Bhatnagar S, Fatora G, Mutyala N, Grande-Allen KJ. Differential cell-matrix responses in hypoxia-stimulated aortic versus mitral valves. J R Soc Interface. 2016;13(125):20160449.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Connolly JM, Bakay MA, Fulmer JT, Gorman RC, Gorman JH 3rd, Oyama MA, Levy RJ. Fenfluramine disrupts the mitral valve interstitial cell response to serotonin. Am J Pathol. 2009;175:988–97.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Hafizi S, Taylor PM, Chester AH, Allen SP, Yacoub MH. Mitogenic and secretory responses of human valve interstitial cells to vasoactive agents. J Heart Valve Dis. 2000;9:454–8.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Jian B, Xu J, Connolly J, Savani RC, Narula N, Liang B, Levy RJ. Serotonin mechanisms in heart valve disease I: serotonin-induced up-regulation of transforming growth factor-beta1 via G-protein signal transduction in aortic valve interstitial cells. Am J Pathol. 2002;161:2111–21.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Rajamannan NM, Caplice N, Anthikad F, Sebo TJ, Orszulak TA, Edwards WD, Tajik J, Schwartz RS. Cell proliferation in carcinoid valve disease: a mechanism for serotonin effects. J Heart Valve Dis. 2001;10:827–31.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Dainese L, Polvani G, Barili F, Maccari F, Guarino A, Alamanni F, Zanobini M, Biglioli P, Volpi N. Fine characterization of mitral valve glycosaminoglycans and their modification with degenerative disease. Clin Chem Lab Med. 2007;45:361–6.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Pham T, Sun W. Material properties of aged human mitral valve leaflets. J Biomed Mater Res A. 2014;102:2692–703.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Obadia JF, Casali C, Chassignolle JF, Janier M. Mitral subvalvular apparatus: different functions of primary and secondary chordae. Circulation. 1997;96:3124–8.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Liao J, Vesely I. Relationship between collagen fibrils, glycosaminoglycans, and stress relaxation in mitral valve chordae tendineae. Ann Biomed Eng. 2004;32:977–83.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Grande-Allen KJ, Griffin BP, Ratliff NB, Cosgrove DM, Vesely I. Glycosaminoglycan profiles of myxomatous mitral leaflets and chordae parallel the severity of mechanical alterations. J Am Coll Cardiol. 2003;42:271–7.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Lincoln J, Alfieri CM, Yutzey KE. BMP and FGF regulatory pathways control cell lineage diversification of heart valve precursor cells. Dev Biol. 2006;292:292–302.PubMedCrossRefGoogle Scholar
  72. 72.
    Dainese L, Guarino A, Micheli B, Biagioli V, Polvani G, Maccari F, Volpi N. Aortic valve leaflet glycosaminoglycans composition and modification in severe chronic valve regurgitation. J Heart Valve Dis. 2013;22:484–90.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Porras AM, Shanmuganayagam D, Meudt JJ, Krueger CG, Hacker TA, Rahko PS, Reed JD, Masters KS. Development of aortic valve disease in familial hypercholesterolemic swine: implications for elucidating disease etiology. J Am Heart Assoc. 2015;4:e002254.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Sider KL, Zhu C, Kwong AV, Mirzaei Z, de Lange CF, Simmons CA. Evaluation of a porcine model of early aortic valve sclerosis. Cardiovasc Pathol. 2014;23:289–97.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Gould RA, Sinha R, Aziz H, Rouf R, Dietz HC 3rd, Judge DP, Butcher J. Multi-scale biomechanical remodeling in aging and genetic mutant murine mitral valve leaflets: insights into Marfan syndrome. PLoS One. 2012;7:e44639.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Hinton RB, Adelman-Brown J, Witt S, Krishnamurthy VK, Osinska H, Sakthivel B, James JF, Li DY, Narmoneva DA, Mecham RP, Benson DW. Elastin haploinsufficiency results in progressive aortic valve malformation and latent valve disease in a mouse model. Circ Res. 2010;107:549–57.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Wilson CL, Gough PJ, Chang CA, Chan CK, Frey JM, Liu Y, Braun KR, Chin MT, Wight TN, Raines EW. Endothelial deletion of ADAM17 in mice results in defective remodeling of the semilunar valves and cardiac dysfunction in adults. Mech Dev. 2013;130:272–89.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Krishnamurthy VK, Guilak F, Narmoneva DA, Hinton RB. Regional structure-function relationships in mouse aortic valve tissue. J Biomech. 2011;44:77–83.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Sewell-Loftin MK, Brown CB, Baldwin HS, Merryman WD. A novel technique for quantifying mouse heart valve leaflet stiffness with atomic force microscopy. J Heart Valve Dis. 2012;21:513–20.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Roberts WC, Honig HS. The spectrum of cardiovascular disease in the Marfan syndrome: a clinico-morphologic study of 18 necropsy patients and comparison to 151 previously reported necropsy patients. Am Heart J. 1982;104:115–35.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Stephens EH, Saltarrelli JG Jr, Balaoing LR, Baggett LS, Nandi I, Anderson KM, Morrisett JD, Reardon MJ, Simpson MA, Weigel PH, Olmsted-Davis EA, Davis AR, Grande-Allen KJ. Hyaluronan turnover and hypoxic brown adipocytic differentiation are co-localized with ossification in calcified human aortic valves. Pathol Res Pract. 2012;208:642–50.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Liu CA, Joag VR, Gotlieb AI. The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology. Am J Pathol. 2007;171:1407–18.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Krishnamurthy VK, Stout AJ, Sapp MC, Matuska B, Lauer ME, Grande-Allen KJ. Dysregulation of hyaluronan homeostasis during aortic valve disease. Matrix Biol. 2017;62:40–57.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Gupta V, Werdenberg JA, Blevins TL, Grande-Allen KJ. Synthesis of glycosaminoglycans in differently loaded regions of collagen gels seeded with valvular interstitial cells. Tissue Eng. 2007;13:41–9.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Gupta V, Werdenberg JA, Mendez JS, Jane Grande-Allen K. Influence of strain on proteoglycan synthesis by valvular interstitial cells in three-dimensional culture. Acta Biomater. 2008;4:88–96.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Gupta V, Werdenberg JA, Lawrence BD, Mendez JS, Stephens EH, Grande-Allen KJ. Reversible secretion of glycosaminoglycans and proteoglycans by cyclically stretched valvular cells in 3D culture. Ann Biomed Eng. 2008;36:1092–103.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Gupta V, Tseng H, Lawrence BD, Grande-Allen KJ. Effect of cyclic mechanical strain on glycosaminoglycan and proteoglycan synthesis by heart valve cells. Acta Biomater. 2009;5:531–40.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Engelmayr GC Jr, Rabkin E, Sutherland FW, Schoen FJ, Mayer JE Jr, Sacks MS. The independent role of cyclic flexure in the early in vitro development of an engineered heart valve tissue. Biomaterials. 2005;26:175–87.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of BioengineeringRice UniversityHoustonUSA

Personalised recommendations