Advertisement

Heart Valve Mechanobiology in Development and Disease

  • Aileen Zhong
  • Craig A. SimmonsEmail author
Chapter
Part of the Physiology in Health and Disease book series (PIHD)

Abstract

Heart valves reside in one of the most mechanically demanding environments within the body, experiencing over 100,000 cycles daily of a combination of biomechanical and hemodynamic forces. The forces applied to heart valves are critical for proper valvulogenesis and normal valve function and maintenance, but disruptions in the mechanical environment can lead to developmental defects and disease. In this chapter, we review current understanding of the roles of hemodynamic forces in valve development, from the initiation of valvulogenesis by cardiac jelly formation, to the invasion of cells into the cardiac cushion through the process of endothelial-to-mesenchymal transition (EndMT) and subsequent remodeling of the extracellular matrix to give rise to the tri-layered structure of developed valves. We also review growing evidence that implicates shear stress, cyclic strain, and matrix mechanics in regulating the initiation and progression of calcific aortic valve disease (CAVD), the most common adult valve disease for which there currently is no medical therapy. An improved understanding of how mechanical forces regulate valve development and disease is expected to help identify therapeutic targets for the treatment of adult valve diseases and to guide the design of living tissue replacement valves for patients with congenital valve defects or diseased valves.

Keywords

Cardiac valve Hemodynamics Valvulogenesis Aortic sclerosis Aortic valve Bicuspid valve 

References

  1. Aikawa E, Whittaker P, Farber M, Mendelson K, Padera RF, Aikawa M et al (2006) Human semilunar cardiac valve remodeling by activated cells from fetus to adult: implications for postnatal adaptation, pathology, and tissue engineering. Circulation 113(10):1344–1352CrossRefPubMedGoogle Scholar
  2. Bäck M, Gasser TC, Michel JB, Caligiuri G (2013) Biomechanical factors in the biology of aortic wall and aortic valve diseases. Cardiovasc Res 99:232–241CrossRefPubMedPubMedCentralGoogle Scholar
  3. Balachandran K, Alford PW, Wylie-Sears J, Goss JA, Grosberg A, Bischoff J et al (2011a) Cyclic strain induces dual-mode endothelial-mesenchymal transformation of the cardiac valve. Proc Natl Acad Sci 108(50):19943–19948CrossRefPubMedPubMedCentralGoogle Scholar
  4. Balachandran K, Bakay MA, Connolly JM, Zhang X, Yoganathan AP, Levy RJ (2011b) Aortic valve cyclic stretch causes increased remodeling activity and enhanced serotonin receptor responsiveness. Ann Thorac Surg 92(1):147–153CrossRefPubMedPubMedCentralGoogle Scholar
  5. Balachandran K, Konduri S, Sucosky P, Jo H, Yoganathan AP (2006) An ex vivo study of the biological properties of porcine aortic valves in response to circumferential cyclic stretch. Ann Biomed Eng 34(11):1655–1665CrossRefPubMedPubMedCentralGoogle Scholar
  6. Balachandran K, Sucosky P, Jo H, Yoganathan AP (2009) 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–H764CrossRefPubMedGoogle Scholar
  7. Balachandran K, Sucosky P, Jo H, Yoganathan AP (2010) Elevated cyclic stretch induces aortic valve calcification in a bone morphogenic protein-dependent manner. Am J Pathol 177(1):49–57CrossRefPubMedPubMedCentralGoogle Scholar
  8. Balachandran K, Sucosky P, Yoganathan AP (2011c) Hemodynamics and mechanobiology of aortic valve inflammation and calcification. Int J Inflam 2011:263870CrossRefPubMedPubMedCentralGoogle Scholar
  9. Banjo T, Grajcarek J, Yoshino D, Osada H, Miyasaka KY, Kida YS et al (2013) Haemodynamically dependent valvulogenesis of zebrafish heart is mediated by flow-dependent expression of miR-21. Nat Commun 4(May):1978PubMedPubMedCentralGoogle Scholar
  10. Bartman T, Walsh EC, Wen KK, McKane M, Ren J, Alexander J et al (2004) Early myocardial function affects endocardial cushion development in zebrafish. PLoS Biol 2(5), E129CrossRefPubMedPubMedCentralGoogle Scholar
  11. Beis D, Bartman T, Jin S-W, Scott IC, D’Amico LA, Ober EA et al (2005) Genetic and cellular analyses of zebrafish atrioventricular cushion and valve development. Development 132(18):4193–4204CrossRefPubMedGoogle Scholar
  12. Blaser MC, Zhou YQ, Falahatpisheh A, Zhang H, Heximer S, Kheradvar A et al (2015) Npr2 deficiency drives aortic valve stenosis, bicuspid aortic valves, ascending aortic dilation, and cardiac dysfunction while preempting aortic valve regurgitation in mice. In: North American Vascular Biology Organization Vascular Biology 2015 Meeting, Hyannis, MAGoogle Scholar
  13. Bouchareb R, Boulanger MC, Fournier D, Pibarot P, Messaddeq Y, Mathieu P (2014) Mechanical strain induces the production of spheroid mineralized microparticles in the aortic valve through a RhoA/ROCK-dependent mechanism. J Mol Cell Cardiol 67:49–59CrossRefPubMedGoogle Scholar
  14. Butcher JT, Markwald RR (2007) Valvulogenesis: the moving target. Philos Trans R Soc Lond B Biol Sci 362(1484):1489–1503CrossRefPubMedPubMedCentralGoogle Scholar
  15. Butcher JT, McQuinn TC, Sedmera D, Turner D, Markwald RR (2007) Transitions in early embryonic atrioventricular valvular function correspond with changes in cushion biomechanics that are predictable by tissue composition. Circ Res 100(10):1503–1511CrossRefPubMedGoogle Scholar
  16. Butcher JT, Nerem RM (2006) Valvular endothelial cells regulate the phenotype of interstitial cells in co-culture: effects of steady shear stress. Tissue Eng 12(4):905–915CrossRefPubMedGoogle Scholar
  17. Butcher JT, Tressel S, Johnson T, Turner D, Sorescu G, Jo H et al (2006) Transcriptional profiles of valvular and vascular endothelial cells reveal phenotypic differences: influence of shear stress. Arterioscler Thromb Vasc Biol 26(1):69–77CrossRefPubMedGoogle Scholar
  18. Carrion K, Dyo J, Patel V, Sasik R, Mohamed SA, Hardiman G et al (2014) The long non-coding HOTAIR is modulated by cyclic stretch and WNT/β-CATENIN in human aortic valve cells and is a novel repressor of calcification genes. PLoS One 9(5):1–7CrossRefGoogle Scholar
  19. Chandra S, Rajamannan NM, Sucosky P (2012) Computational assessment of bicuspid aortic valve wall-shear stress: implications for calcific aortic valve disease. Biomech Model Mechanobiol 11(7):1085–1096CrossRefPubMedGoogle Scholar
  20. Chen JH, Chen WLK, Sider KL, Yip CYY, Simmons CA (2011) β-catenin mediates mechanically regulated, transforming growth factor-β1-induced myofibroblast differentiation of aortic valve interstitial cells. Arterioscler Thromb Vasc Biol 31(3):590–597Google Scholar
  21. Chen JH, Simmons CA (2011) Cell-matrix interactions in the pathobiology of calcific aortic valve disease: critical roles for matricellular, matricrine, and matrix mechanics cues. Circ Res 108(12):1510–1524CrossRefPubMedGoogle Scholar
  22. Chen JH, Yip CYY, Sone ED, Simmons CA (2009) Identification and characterization of aortic valve mesenchymal progenitor cells with robust osteogenic calcification potential. Am J Pathol 174(3):1109–1119CrossRefPubMedPubMedCentralGoogle Scholar
  23. Chen MB, Srigunapalan S, Wheeler AR, Simmons CA (2013) A 3D microfluidic platform incorporating methacrylated gelatin hydrogels to study physiological cardiovascular cell–cell interactions. Lab Chip 13(13):2591CrossRefPubMedGoogle Scholar
  24. Combs MD, Yutzey KE (2009) Heart valve development: regulatory networks in development and disease. Circ Res 105(5):408–421CrossRefPubMedPubMedCentralGoogle Scholar
  25. Dal-Bianco JP, Aikawa E, Bischoff J, Guerrero JL, Handschumacher MD, Sullivan S et al (2009) Active adaptation of the tethered mitral valve: insights into a compensatory mechanism for functional mitral regurgitation. Circulation 120(4):334–342CrossRefPubMedPubMedCentralGoogle Scholar
  26. Engler AJ, Sen S, Sweeney HL, Discher DE (2006) Matrix elasticity directs stem cell lineage specification. Cell 126(4):677–689CrossRefPubMedGoogle Scholar
  27. Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN et al (2005) Mutations in NOTCH1 cause aortic valve disease. Nature 437(7056):270–274CrossRefPubMedGoogle Scholar
  28. Gould ST, Matherly EE, Smith JN, Heistad DD, Anseth KS (2014) The role of valvular endothelial cell paracrine signaling and matrix elasticity on valvular interstitial cell activation. Biomaterials 35(11):3596–3606CrossRefPubMedPubMedCentralGoogle Scholar
  29. Gould ST, Srigunapalan S, Simmons CA, Anseth KS (2013) Hemodynamic and cellular response feedback in calcific aortic valve disease. Circ Res 113(2):186–197CrossRefPubMedGoogle Scholar
  30. Groenendijk BCW, Hierck BP, Vrolijk J, Baiker M, Pourquie MJBM, Gittenberger-De Groot AC et al (2005) Changes in shear stress-related gene expression after experimentally altered venous return in the chicken embryo. Circ Res 96(12):1291–1298CrossRefPubMedGoogle Scholar
  31. Guerraty MA, Grant GR, Karanian JW, Chiesa OA, Pritchard WF, Davies PF (2010) Hypercholesterolemia induces side-specific phenotypic changes and peroxisome proliferator-activated receptor-gamma pathway activation in swine aortic valve endothelium. Arterioscler Thromb Vasc Biol 30(2):225–231CrossRefPubMedGoogle Scholar
  32. Heckel E, Boselli F, Roth S, Krudewig A, Belting H-G, Charvin G et al (2015) Oscillatory flow modulates mechanosensitive klf2a expression through trpv4 and trpp2 during heart valve development. Curr Biol 25:1354–1361CrossRefPubMedGoogle Scholar
  33. Hinton RB, Yutzey KE (2011) Heart valve structure and function in development and disease. Annu Rev Physiol 73(73):29–46CrossRefPubMedPubMedCentralGoogle Scholar
  34. Hoffman JI, Kaplan S (2002) The incidence of congenital heart disease. J Am Coll Cardiol 39(12):1890–1900CrossRefPubMedGoogle Scholar
  35. Holliday CJ, Ankeny RF, Jo H, Nerem RM (2011) Discovery of shear- and side-specific mRNAs and miRNAs in human aortic valvular endothelial cells. Am J Physiol Heart Circ Physiol 301(3):H856–H867CrossRefPubMedPubMedCentralGoogle Scholar
  36. Hove JR, Köster RW, Forouhar AS, Acevedo-Bolton G, Fraser SE, Gharib M (2003) Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis. Nature 421(6919):172–177CrossRefPubMedGoogle Scholar
  37. Hutcheson JD, Venkataraman R, Baudenbacher FJ, David W (2012) Intracellular Ca2+ accumulation is strain-dependent and correlates with apoptosis in aortic valve fibroblasts. J Biomech 45(5):888–894Google Scholar
  38. Hutcheson JD, Chen J, Sewell-Loftin MK, Ryzhova LM, Fisher CI, Su YR et al (2013) Cadherin-11 regulates cell-cell tension necessary for calcific nodule formation by valvular myofibroblasts. Arterioscler Thromb Vasc Biol 33:114–120CrossRefPubMedGoogle Scholar
  39. Katayama S, Umetani N, Hisada T, Sugiura S (2013) Bicuspid aortic valves undergo excessive strain during opening: a simulation study. J Thorac Cardiovasc Surg 145(6):1570–1576CrossRefPubMedGoogle Scholar
  40. Kennedy JA, Hua X, Mishra K, Murphy GA, Rosenkranz AC, Horowitz JD (2009) Inhibition of calcifying nodule formation in cultured porcine aortic valve cells by nitric oxide donors. Eur J Pharmacol 602(1):28–35CrossRefPubMedGoogle Scholar
  41. Ku C-H, Johnson PH, Batten P, Sarathchandra P, Chambers RC, Taylor PM et al (2006) Collagen synthesis by mesenchymal stem cells and aortic valve interstitial cells in response to mechanical stretch. Cardiovasc Res 71(3):548–556CrossRefPubMedGoogle Scholar
  42. Li C, Xu S, Gotlieb AI (2013) The progression of calcific aortic valve disease through injury, cell dysfunction, and disruptive biologic and physical force feedback loops. Cardiovasc Pathol 22(1):1–8CrossRefPubMedGoogle Scholar
  43. Lindroos M, Kupari M, Heikkilä J, Tilvis R (1993) Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. J Am Coll Cardiol 21(5):1220–1225CrossRefPubMedGoogle Scholar
  44. Lindsey SE (2014) Mechanical regulation of cardiac development. Front Physiol 5(August):1–15Google Scholar
  45. Lindsey SE, Butcher JT (2011) The cycle of form and function in cardiac valvulogenesis. Aswan Hear Cent Sci Pract Ser 2011(2):10CrossRefGoogle Scholar
  46. Masumura T, Yamamoto K, Shimizu N, Obi S, Ando J (2009) Shear stress increases expression of the arterial endothelial marker ephrinB2 in murine ES cells via the VEGF-notch signaling pathways. Arterioscler Thromb Vasc Biol 29(12):2125–2131CrossRefPubMedGoogle Scholar
  47. Mathieu P, Boulanger M-C, Bouchareb R (2014) Molecular biology of calcific aortic valve disease: towards new pharmacological therapies. Expert Rev Cardiovasc Ther 12(7):851–862Google Scholar
  48. Merryman WD, Youn I, Lukoff HD, Krueger PM, Guilak F, Hopkins RA, Sacks MS (2006) Correlation between heart valve interstitial cell stiffness and transvalvular pressure: implications for collagen biosynthesis. Am J Physiol Heart Circ Physiol. 290(1):H224–31Google Scholar
  49. Merryman WD, Liao J, Parekh A, Candiello JE, Lin H, Sacks MS. (2007a) Differences in tissue-remodeling potential of aortic and pulmonary heart valve interstitial cells. Tissue Eng. 13(9):2281–2289Google Scholar
  50. Merryman WD, Lukoff HD, Long RA, Engelmayr GC Jr, Hopkins RA, Sacks MS (2007b) Synergistic effects of cyclic tension and transforming growth factor-beta1 on the aortic valve myofibroblast. Cardiovasc Pathol 16(5):268–276Google Scholar
  51. Mohamed SA, Radtke A, Saraei R, Bullerdiek J, Sorani H, Nimzyk R et al (2012) Locally different endothelial nitric oxide synthase protein levels in ascending aortic aneurysms of bicuspid and tricuspid aortic valve. Cardiol Res Pract 2012:165957PubMedPubMedCentralGoogle Scholar
  52. Mohler ER, Gannon F, Reynolds C, Zimmerman R, Keane MG, Kaplan FS (2001) Bone formation and inflammation in cardiac valves. Circulation 103(11):1522–1528CrossRefPubMedGoogle Scholar
  53. Moraes C, Likhitpanichkul M, Lam CJ, Beca BM, Sun Y, Simmons CA (2013) Microdevice array-based identification of distinct mechanobiological response profiles in layer-specific valve interstitial cells. Integr Biol (Camb) 5(4):673–680CrossRefGoogle Scholar
  54. Nishimura RA (2002) Aortic valve disease. Circulation 106(7):770–772CrossRefPubMedGoogle Scholar
  55. Otto CM, Kuusisto J, Reichenbach DD, Gown AM, O’Brien KD (1994) Characterization of the early lesion of “degenerative” valvular aortic stenosis. Histological and immunohistochemical studies. Circulation 90(2):844–853CrossRefPubMedGoogle Scholar
  56. Parvin Nejad S, Blaser MC, Santerre JP, Caldarone CA, Simmons CA (2016) Biomechanical conditioning of tissue engineered heart valves: too much of a good thing? Adv Drug Deliv Rev 96:161–175CrossRefPubMedGoogle Scholar
  57. Patel V, Carrion K, Hollands A, Hinton A, Gallegos T, Dyo J et al (2015) The stretch responsive microRNA miR-148a-3p is a novel repressor of IKBKB, NF-κB signaling, and inflammatory gene expression in human aortic valve cells. FASEB J 29:1859–1868Google Scholar
  58. Person AD, Klewer SE, Runyan RB (2005) Cell biology of cardiac cushion development. Int Rev Cytol 243:287–335CrossRefPubMedGoogle Scholar
  59. Peterson LM, Jenkins MW, Gu S, Barwick L, Watanabe M, Rollins AM (2012) 4D shear stress maps of the developing heart using Doppler optical coherence tomography. Biomed Opt Express 3(11):3022CrossRefPubMedPubMedCentralGoogle Scholar
  60. Pho M, Lee W, Watt DR, Laschinger C, Simmons CA, McCulloch CA (2008) Cofilin is a marker of myofibroblast differentiation in cells from porcine aortic cardiac valves. Am J Physiol Heart Circ Physiol 294(4):H1767–H1778CrossRefPubMedGoogle Scholar
  61. Rajamannan NM, Sangiorgi G, Springett M, Arnold K, Mohacsi T, Spagnoli LG et al (2001) Experimental hypercholesterolemia induces apoptosis in the aortic valve. J Heart Valve Dis 10(3):371–374PubMedGoogle Scholar
  62. Rajamannan NM, Evans FJ, Aikawa E, Grande-Allen KJ, Demer LL, Heistad DD et al (2011) Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: calcific aortic valve disease-2011 update. Circulation 124(16):1783–1791CrossRefPubMedPubMedCentralGoogle Scholar
  63. Rajamannan NM, Subramaniam M, Rickard D, Stock SR, Donovan J, Springett M et al (2003) Human aortic valve calcification is associated with an osteoblast phenotype. Circulation 107(17):2181–2184CrossRefPubMedPubMedCentralGoogle Scholar
  64. Richards J, El-Hamamsy I, Chen S, Sarang Z, Sarathchandra P, Yacoub MH et al (2013) Side-specific endothelial-dependent regulation of aortic valve calcification. Am J Pathol 182(5):1922–1931CrossRefPubMedPubMedCentralGoogle Scholar
  65. Riem Vis PW, Kluin J, Sluijter JPG, van Herwerden LA, Bouten CVC (2011) Environmental regulation of valvulogenesis: implications for tissue engineering. Eur J Cardiothorac Surg 39(1):8–17CrossRefPubMedGoogle Scholar
  66. Savolainen SM, Foley JF, Elmore SA (2009) Histology atlas of the developing mouse heart with emphasis on E11.5 to E18.5. Toxicol Pathol 37(4):395–414CrossRefPubMedPubMedCentralGoogle Scholar
  67. Sewell-Loftin M-K, Brown CB, Baldwin HS, Merryman WD (2012) A novel technique for quantifying mouse heart valve leaflet stiffness with atomic force microscopy. J Heart Valve Dis 21(4):513–520PubMedPubMedCentralGoogle Scholar
  68. Sider KL, Blaser MC, Simmons CA (2011) Animal models of calcific aortic valve disease. Int J Inflam 2011:364310CrossRefPubMedPubMedCentralGoogle Scholar
  69. Simmons CA, Grant GR, Manduchi E, Davies PF (2005) Spatial heterogeneity of endothelial phenotypes correlates with side-specific vulnerability to calcification in normal porcine aortic valves. Circ Res 96(7):792–799CrossRefPubMedPubMedCentralGoogle Scholar
  70. Siu SC, Silversides CK (2010) Bicuspid aortic valve disease. J Am Coll Cardiol 55(25):2789–2800CrossRefPubMedGoogle Scholar
  71. Stephens EH, Chu CK, Grande-Allen KJ (2008) 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 4(5):1148–1160CrossRefPubMedGoogle Scholar
  72. Sucosky P, Balachandran K, Elhammali A, Jo H, Yoganathan AP (2008) Altered shear stress stimulates upregulation of endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-β1-dependent pathway. Arterioscler Thromb Vasc Biol 29(2):254–260CrossRefPubMedGoogle Scholar
  73. Sun L, Chandra S, Sucosky P (2012) Ex vivo evidence for the contribution of hemodynamic shear stress abnormalities to the early pathogenesis of calcific bicuspid aortic valve disease. PLoS One 7(10), e48843CrossRefPubMedPubMedCentralGoogle Scholar
  74. Szeto K, Pastuszko P, del Alamo JC, Lasheras J, Nigam V (2013) Bicuspid aortic valves experience increased strain as compared to tricuspid aortic valves. World J Pediatr Congenit Heart Surg 4(4):362–366CrossRefPubMedGoogle Scholar
  75. Theodoris CV, Li M, White MPP, Liu L, He D, Pollard KSS et al (2015) Human disease modeling reveals integrated transcriptional and epigenetic mechanisms of NOTCH1 haploinsufficiency. Cell 160(6):1072–1086CrossRefPubMedPubMedCentralGoogle Scholar
  76. Thubrikar MJ (1990) Mechanical stresses in the aortic valve. CRC Press, Boca Raton, FLGoogle Scholar
  77. Vermot J, Forouhar AS, Liebling M, Wu D, Plummer D, Gharib M et al (2009) Reversing blood flows act through klf2a to ensure normal valvulogenesis in the developing heart. PLoS Biol 7(11):12–14CrossRefGoogle Scholar
  78. Vesely I, Noseworthy R (1992) Micromechanics of the fibrosa and the ventricularis in aortic valve leaflets. J Biomech 25(1):101–113CrossRefPubMedGoogle Scholar
  79. Warnock JN, Nanduri B, Pregonero Gamez CA, Tang J, Koback D, Muir WM et al (2011) Gene profiling of aortic valve interstitial cells under elevated pressure conditions: modulation of inflammatory gene networks. Int J Inflam 2011:176412CrossRefPubMedPubMedCentralGoogle Scholar
  80. Weiler M, Hwai Yap C, Balachandran K, Muralidhar P, Yoganathan AP, Padala M et al (2011) Regional analysis of dynamic deformation characteristics of native aortic valve leaflets. J Biomech 44(8):1459–1465CrossRefPubMedPubMedCentralGoogle Scholar
  81. Weston MW, LaBorde DV, Yoganathan AP (1999) Estimation of the shear stress on the surface of an aortic valve leaflet. Ann Biomed Eng 27(4):572–579CrossRefPubMedGoogle Scholar
  82. Wirrig EE, Yutzey KE (2014) Conserved transcriptional regulatory mechanisms in aortic valve development and disease. Arterioscler Thromb Vasc Biol 34:737–741CrossRefPubMedPubMedCentralGoogle Scholar
  83. Wyss K, Yip CYY, Mirzaei Z, Jin X, Chen JH, Simmons CA (2012) The elastic properties of valve interstitial cells undergoing pathological differentiation. J Biomech 45(5):882–887CrossRefPubMedGoogle Scholar
  84. Yalcin HC, Shekhar A, McQuinn TC, Butcher JT (2011) Hemodynamic patterning of the avian atrioventricular valve. Dev Dyn 240(1):23–35CrossRefPubMedPubMedCentralGoogle Scholar
  85. Yap CH, Kim H-S, Balachandran K, Weiler M, Haj-Ali R, Yoganathan AP et al (2010) Dynamic deformation characteristics of porcine aortic valve leaflet under normal and hypertensive conditions. Am J Physiol Heart Circ Physiol 298(5):395–405CrossRefGoogle Scholar
  86. Yap CH, Saikrishnan N, Tamilselvan G, Vasilyev N, Yoganathan AP (2012a) The congenital bicuspid aortic valve can experience high frequency unsteady shear stresses on its leaflet surface. Am J Physiol Heart Circ Physiol 303:H721–H731CrossRefPubMedPubMedCentralGoogle Scholar
  87. Yap CH, Saikrishnan N, Yoganathan AP (2012b) Experimental measurement of dynamic fluid shear stress on the ventricular surface of the aortic valve leaflet. Biomech Model Mechanobiol 11:231–244CrossRefPubMedGoogle Scholar
  88. Yip CYY, Blaser MC, Mirzaei Z, Zhong X, Simmons CA (2011) Inhibition of pathological differentiation of valvular interstitial cells by C-type natriuretic peptide. Arterioscler Thromb Vasc Biol 31(8):1881–1889CrossRefPubMedGoogle Scholar
  89. Yip CYY, Chen JH, Zhao R, Simmons CA (2009) Calcification by valve interstitial cells is regulated by the stiffness of the extracellular matrix. Arterioscler Thromb Vasc Biol 29(6):936–942CrossRefPubMedGoogle Scholar
  90. Yip CYY, Simmons CA (2011) The aortic valve microenvironment and its role in calcific aortic valve disease. Cardiovasc Pathol 20(3):177–182CrossRefPubMedGoogle Scholar
  91. Yutzey KE, Demer LL, Body SC, Huggins GS, Towler DA, Giachelli CM et al (2014) Calcific aortic valve disease: a consensus summary from the alliance of investigators on calcific aortic valve disease. Arterioscler Thromb Vasc Biol 34(11):2387–2393CrossRefPubMedPubMedCentralGoogle Scholar
  92. Zhang Z, Xiao Z, Diamond SL (1999) Shear stress induction of C-type natriuretic peptide (CNP) in endothelial cells is independent of NO autocrine signaling. Ann Biomed Eng 27(4):419–426CrossRefPubMedGoogle Scholar
  93. Zhao R, Sider KL, Simmons CA (2011) Measurement of layer-specific mechanical properties in multilayered biomaterials by micropipette aspiration. Acta Biomater 7(3):1220–1227CrossRefPubMedGoogle Scholar

Copyright information

© The American Physiological Society 2016

Authors and Affiliations

  1. 1.Translational Biology and Engineering ProgramTed Rogers Centre for Heart ResearchTorontoCanada
  2. 2.Institute of Biomaterials and Biomedical EngineeringUniversity of TorontoTorontoCanada
  3. 3.Department of Mechanical and Industrial EngineeringUniversity of TorontoTorontoCanada

Personalised recommendations