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Endothelial Mechanotransduction

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Advances in Heart Valve Biomechanics

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Abstract

The aortic valve resides in a dynamic mechanical environment, with constant exposure to fluid shear stresses and cyclic strain. These physical forces directly impact the valve endothelium and these cells will regulate the biological response of the valve. Under normal physiological conditions, the endothelium provides a monolayer that protects the valve tissue. However, under abnormal conditions, a cascade of events can lead to a loss of integrity in the endothelium, expression of pro-inflammatory molecules that recruit monocytes to the tissue and paracrine signaling that could cause degradation of the valve tissue and extracellular matrix. Understanding the molecular events caused by changes in the mechanical environment is paramount in the identification of biomolecular markers for disease diagnosis and in the development of novel therapeutic strategies that could alleviate the need for surgical intervention.

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References

  1. Mofrad MR, Kamm RD. Cellular mechanotransduction: diverse perspectives from molecules to tissues. Cambridge: Cambridge University Press; 2009.

    Book  Google Scholar 

  2. Konduri S, Xing Y, Warnock JN, He Z, Yoganathan AP. Normal physiological conditions maintain the biological characteristics of porcine aortic heart valves: an ex vivo organ culture study. Ann Biomed Eng. 2005;33(9):1158–66.

    Article  PubMed  Google Scholar 

  3. Smith KE, Metzler SA, Warnock JN. Cyclic strain inhibits acute pro-inflammatory gene expression in aortic valve interstitial cells. Biomech Model Mechanobiol. 2010;9(1):117–25.

    Article  PubMed  Google Scholar 

  4. Back M, Gasser TC, Michel JB, Caligiuri G. Biomechanical factors in the biology of aortic wall and aortic valve diseases. Cardiovasc Res. 2013;99(2):232–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Balachandran K, Konduri S, Sucosky P, Jo H, Yoganathan AP. An ex vivo study of the biological properties of porcine aortic valves in response to circumferential cyclic stretch. Ann Biomed Eng. 2006;34(11):1655–65.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Fisher CI, Chen J, Merryman WD. Calcific nodule morphogenesis by heart valve interstitial cells is strain dependent. Biomech Model Mechanobiol. 2013;12(1):5–17.

    Article  PubMed  Google Scholar 

  7. Merryman WD, Schoen FJ. Mechanisms of calcification in aortic valve disease: role of mechanokinetics and mechanodynamics. Curr Cardiol Rep. 2013;15(5):355.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Metzler SA, Digesu CS, Howard JI, Filip To SD, Warnock JN. Live en face imaging of aortic valve leaflets under mechanical stress. Biomech Model Mechanobiol. 2012;11(3–4):355–61.

    Article  PubMed  Google Scholar 

  9. Metzler SA, Pregonero CA, Butcher JT, Burgess SC, Warnock JN. Cyclic strain regulates pro-inflammatory protein expression in porcine aortic valve endothelial cells. J Heart Valve Dis. 2008;17(5):571–7; discussion 8.

    PubMed  Google Scholar 

  10. Heckel E, Boselli F, Roth S, Krudewig A, Belting HG, Charvin G, et al. Oscillatory flow modulates mechanosensitive klf2a expression through trpv4 and trpp2 during heart valve development. Curr Biol. 2015;25(10):1354–61.

    Article  CAS  PubMed  Google Scholar 

  11. Tan H, Biechler S, Junor L, Yost MJ, Dean D, Li J, et al. Fluid flow forces and rhoA regulate fibrous development of the atrioventricular valves. Dev Biol. 2013;374(2):345–56.

    Article  CAS  PubMed  Google Scholar 

  12. Nicosia MA, Cochran RP, Einstein DR, Rutland CJ, Kunzelman KS. A coupled fluid-structure finite element model of the aortic valve and root. J Heart Valve Dis. 2003;12(6):781–9.

    PubMed  Google Scholar 

  13. Ge L, Sotiropoulos F. Direction and magnitude of blood flow shear stresses on the leaflets of aortic valves: is there a link with valve calcification? J Biomech Eng. 2010;132(1):014505.

    Article  PubMed  Google Scholar 

  14. Weston MW, LaBorde DV, Yoganathan AP. Estimation of the shear stress on the surface of an aortic valve leaflet. Ann Biomed Eng. 1999;27(4):572–9.

    Article  CAS  PubMed  Google Scholar 

  15. Yap CH, Saikrishnan N, Yoganathan AP. Experimental measurement of dynamic fluid shear stress on the ventricular surface of the aortic valve leaflet. Biomech Model Mechanobiol. 2012;11(1–2):231–44.

    Article  PubMed  Google Scholar 

  16. Yap CH, Saikrishnan N, Tamilselvan G, Yoganathan AP. Experimental measurement of dynamic fluid shear stress on the aortic surface of the aortic valve leaflet. Biomech Model Mechanobiol. 2012;11(1–2):171–82.

    Article  PubMed  Google Scholar 

  17. Yap CH, Kim HS, Balachandran K, Weiler M, Haj-Ali R, Yoganathan AP. Dynamic deformation characteristics of porcine aortic valve leaflet under normal and hypertensive conditions. Am J Physiol Heart Circ Physiol. 2010;298(2):H395–405.

    Article  CAS  PubMed  Google Scholar 

  18. Loufrani L, Retailleau K, Bocquet A, Dumont O, Danker K, Louis H, et al. Key role of alpha(1)beta(1)-integrin in the activation of PI3-kinase-Akt by flow (shear stress) in resistance arteries. Am J Physiol Heart Circ Physiol. 2008;294(4):H1906–13.

    Article  CAS  PubMed  Google Scholar 

  19. Jalali S, del Pozo MA, Chen K, Miao H, Li Y, Schwartz MA, et al. Integrin-mediated mechanotransduction requires its dynamic interaction with specific extracellular matrix (ECM) ligands. Proc Natl Acad Sci U S A. 2001;98(3):1042–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen KD, Li YS, Kim M, Li S, Yuan S, Chien S, et al. Mechanotransduction in response to shear stress. Roles of receptor tyrosine kinases, integrins, and Shc. J Biol Chem. 1999;274(26):18393–400.

    Article  CAS  PubMed  Google Scholar 

  21. Muller JM, Chilian WM, Davis MJ. Integrin signaling transduces shear stress-dependent vasodilation of coronary arterioles. Circ Res. 1997;80(3):320–6.

    Article  CAS  PubMed  Google Scholar 

  22. Tzima E, del Pozo MA, Shattil SJ, Chien S, Schwartz MA. Activation of integrins in endothelial cells by fluid shear stress mediates Rho-dependent cytoskeletal alignment. EMBO J. 2001;20(17):4639–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang Y, Miao H, Li S, Chen KD, Li YS, Yuan S, et al. Interplay between integrins and FLK-1 in shear stress-induced signaling. Am J Physiol Cell Physiol. 2002;283(5):C1540–7.

    Article  CAS  PubMed  Google Scholar 

  24. Brakemeier S, Kersten A, Eichler I, Grgic I, Zakrzewicz A, Hopp H, et al. Shear stress-induced up-regulation of the intermediate-conductance Ca(2+)-activated K(+) channel in human endothelium. Cardiovasc Res. 2003;60(3):488–96.

    Article  CAS  PubMed  Google Scholar 

  25. Lieu DK, Pappone PA, Barakat AI. Differential membrane potential and ion current responses to different types of shear stress in vascular endothelial cells. Am J Physiol Cell Physiol. 2004;286(6):C1367–75.

    Article  CAS  PubMed  Google Scholar 

  26. Olesen SP, Clapham DE, Davies PF. Haemodynamic shear stress activates a K+ current in vascular endothelial cells. Nature. 1988;331(6152):168–70.

    Article  CAS  PubMed  Google Scholar 

  27. Naruse K, Sai X, Yokoyama N, Sokabe M. Uni-axial cyclic stretch induces c-src activation and translocation in human endothelial cells via SA channel activation. FEBS Lett. 1998;441(1):111–5.

    Article  CAS  PubMed  Google Scholar 

  28. Naruse K, Sokabe M. Involvement of stretch-activated ion channels in Ca2+ mobilization to mechanical stretch in endothelial cells. Am J Phys. 1993;264(4 Pt 1):C1037–44.

    Article  CAS  Google Scholar 

  29. Naruse K, Yamada T, Sokabe M. Involvement of SA channels in orienting response of cultured endothelial cells to cyclic stretch. Am J Phys. 1998;274(5 Pt 2):H1532–8.

    CAS  Google Scholar 

  30. Tatsukawa Y, Kiyosue T, Arita M. Mechanical stretch increases intracellular calcium concentration in cultured ventricular cells from neonatal rats. Heart Vessel. 1997;12(3):128–35.

    Article  CAS  Google Scholar 

  31. Jin ZG, Wong C, Wu J, Berk BC. Flow shear stress stimulates Gab1 tyrosine phosphorylation to mediate protein kinase B and endothelial nitric-oxide synthase activation in endothelial cells. J Biol Chem. 2005;280(13):12305–9.

    Article  CAS  PubMed  Google Scholar 

  32. Otte LA, Bell KS, Loufrani L, Yeh JC, Melchior B, Dao DN, et al. Rapid changes in shear stress induce dissociation of a G alpha(q/11)-platelet endothelial cell adhesion molecule-1 complex. J Physiol. 2009;587.(Pt 10:2365–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang S, Iring A, Strilic B, Albarran Juarez J, Kaur H, Troidl K, et al. P2Y(2) and Gq/G(1)(1) control blood pressure by mediating endothelial mechanotransduction. J Clin Invest. 2015;125(8):3077–86.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Zeng H, Zhao D, Yang S, Datta K, Mukhopadhyay D. Heterotrimeric G alpha q/G alpha 11 proteins function upstream of vascular endothelial growth factor (VEGF) receptor-2 (KDR) phosphorylation in vascular permeability factor/VEGF signaling. J Biol Chem. 2003;278(23):20738–45.

    Article  CAS  PubMed  Google Scholar 

  35. Secomb TW, Hsu R, Pries AR. Effect of the endothelial surface layer on transmission of fluid shear stress to endothelial cells. Biorheology. 2001;38(2–3):143–50.

    CAS  PubMed  Google Scholar 

  36. Weinbaum S, Zhang X, Han Y, Vink H, Cowin SC. Mechanotransduction and flow across the endothelial glycocalyx. Proc Natl Acad Sci U S A. 2003;100(13):7988–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch. 2007;454(3):345–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Salmon AH, Satchell SC. Endothelial glycocalyx dysfunction in disease: albuminuria and increased microvascular permeability. J Pathol. 2012;226(4):562–74.

    Article  CAS  PubMed  Google Scholar 

  39. Tarbell JM, Ebong EE. The endothelial glycocalyx: a mechano-sensor and -transducer. Sci Signal. 2008;1(40):pt8.

    Article  PubMed  Google Scholar 

  40. Tarbell JM, Pahakis MY. Mechanotransduction and the glycocalyx. J Intern Med. 2006;259(4):339–50.

    Article  CAS  PubMed  Google Scholar 

  41. Smith ML, Long DS, Damiano ER, Ley K. Near-wall micro-PIV reveals a hydrodynamically relevant endothelial surface layer in venules in vivo. Biophys J. 2003;85(1):637–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Davies P, Helmke B. Endothelial mechanotransduction. In: Mofrad MR, Kamm RD, editors. Cellular mechanotransduction. New York: Cambridge University Press; 2009.

    Google Scholar 

  43. Ingber DE. Cellular mechanotransduction: putting all the pieces together again. FASEB J. 2006;20(7):811–27.

    Article  CAS  PubMed  Google Scholar 

  44. Ingber DE, Wang N, Stamenovic D. Tensegrity, cellular biophysics, and the mechanics of living systems. Rep Prog Phys. 2014;77(4):046603.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Conway DE, Breckenridge MT, Hinde E, Gratton E, Chen CS, Schwartz MA. Fluid shear stress on endothelial cells modulates mechanical tension across VE-cadherin and PECAM-1. Curr Biol. 2013;23(11):1024–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Coon BG, Baeyens N, Han J, Budatha M, Ross TD, Fang JS, et al. Intramembrane binding of VE-cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex. J Cell Biol. 2015;208(7):975–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tzima E, Irani-Tehrani M, Kiosses WB, Dejana E, Schultz DA, Engelhardt B, et al. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature. 2005;437(7057):426–31.

    Article  CAS  PubMed  Google Scholar 

  48. Helmke BP, Davies PF. The cytoskeleton under external fluid mechanical forces: hemodynamic forces acting on the endothelium. Ann Biomed Eng. 2002;30(3):284–96.

    Article  PubMed  Google Scholar 

  49. Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, et al. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol. 1997;29(3):630–4.

    Article  CAS  PubMed  Google Scholar 

  50. O'Brien KD. Pathogenesis of calcific aortic valve disease: a disease process comes of age (and a good deal more). Arterioscler Thromb Vasc Biol. 2006;26(8):1721–8.

    Article  CAS  PubMed  Google Scholar 

  51. Elmariah S, Mohler ER 3rd. The pathogenesis and treatment of the valvulopathy of aortic stenosis: beyond the SEAS. Curr Cardiol Rep. 2010;12(2):125–32.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Kaden JJ, Dempfle CE, Grobholz R, Tran HT, Kilic R, Sarikoc A, et al. Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis. Atherosclerosis. 2003;170(2):205–11.

    Article  CAS  PubMed  Google Scholar 

  53. Edep ME, Shirani J, Wolf P, Brown DL. Matrix metalloproteinase expression in nonrheumatic aortic stenosis. Cardiovasc Pathol. 2000;9(5):281–6.

    Article  CAS  PubMed  Google Scholar 

  54. Kaden JJ, Vocke DC, Fischer CS, Grobholz R, Brueckmann M, Vahl CF, et al. Expression and activity of matrix metalloproteinase-2 in calcific aortic stenosis. Z Kardiol. 2004;93(2):124–30.

    Article  CAS  PubMed  Google Scholar 

  55. Soini Y, Satta J, Maatta M, Autio-Harmainen H. Expression of MMP2, MMP9, MT1-MMP, TIMP1, and TIMP2 mRNA in valvular lesions of the heart. J Pathol. 2001;194(2):225–31.

    Article  CAS  PubMed  Google Scholar 

  56. Chen JH, Simmons CA. Cell-matrix interactions in the pathobiology of calcific aortic valve disease: critical roles for matricellular, matricrine, and matrix mechanics cues. Circ Res. 2011;108(12):1510–24.

    Article  CAS  PubMed  Google Scholar 

  57. Hinton RB Jr, Lincoln J, Deutsch GH, Osinska H, Manning PB, Benson DW, et al. Extracellular matrix remodeling and organization in developing and diseased aortic valves. Circ Res. 2006;98(11):1431–8.

    Article  CAS  PubMed  Google Scholar 

  58. Otto CM, Kuusisto J, Reichenbach DD, Gown AM, O'Brien KD. Characterization of the early lesion of ‘degenerative’ valvular aortic stenosis. Histological and immunohistochemical studies. Circulation. 1994;90(2):844–53.

    Article  CAS  PubMed  Google Scholar 

  59. Butcher JT, Nerem RM. Valvular endothelial cells and the mechanoregulation of valvular pathology. Philos Trans R Soc B Biol Sci. 2007;362(1484):1445–57.

    Article  CAS  Google Scholar 

  60. Agmon Y, Khandheria BK, Meissner I, Sicks JR, O'Fallon WM, Wiebers DO, et al. Aortic valve sclerosis and aortic atherosclerosis: different manifestations of the same disease? Insights from a population-based study. J Am Coll Cardiol. 2001;38(3):827–34.

    Article  CAS  PubMed  Google Scholar 

  61. Mohler ER 3rd. Mechanisms of aortic valve calcification. Am J Cardiol. 2004;94(11):1396–402. A6

    Article  PubMed  Google Scholar 

  62. Otto CM, O'Brien KD. Why is there discordance between calcific aortic stenosis and coronary artery disease? Heart. 2001;85(6):601–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Butcher JT, Mahler GJ, Hockaday LA. Aortic valve disease and treatment: the need for naturally engineered solutions. Adv Drug Deliv Rev. 2011;63(4–5):242–68.

    Article  CAS  PubMed  Google Scholar 

  64. Davies P, Reidy M, Goode T, Bowyer D. Scanning electron microscopy in the evaluation of endothelial integrity of the fatty lesion in atherosclerosis. Atherosclerosis. 1976;25(1):125–30.

    Article  CAS  PubMed  Google Scholar 

  65. Reinhart-King CA, Fujiwara K, Berk BC. Physiologic stress-mediated signaling in the endothelium. Methods Enzymol. 2008;443:25–44.

    Article  CAS  PubMed  Google Scholar 

  66. Frangos J, Eskin S, McIntire L, Ives C. Flow effects on prostacyclin production by cultured human endothelial cells. Science. 1985;227(4693):1477–9.

    Article  CAS  PubMed  Google Scholar 

  67. Levesque MJ, Nerem RM. The elongation and orientation of cultured endothelial cells in response to shear stress. J Biomech Eng. 1985;107(4):341–7.

    Article  CAS  PubMed  Google Scholar 

  68. Butcher JT, Penrod AM, Garcia AJ, Nerem RM. Unique morphology and focal adhesion development of valvular endothelial cells in static and fluid flow environments. Arterioscler Thromb Vasc Biol. 2004;24(8):1429–34.

    Article  CAS  PubMed  Google Scholar 

  69. Davies PF, Passerini AG, Simmons CA. Aortic valve: turning over a new leaf(let) in endothelial phenotypic heterogeneity. Arterioscler Thromb Vasc Biol. 2004;24(8):1331–3.

    Article  CAS  PubMed  Google Scholar 

  70. Butcher JT, Tressel S, Johnson T, Turner D, Sorescu G, Jo H, et al. Transcriptional profiles of valvular and vascular endothelial cells reveal phenotypic differences: influence of shear stress. Arterioscler Thromb Vasc Biol. 2006;26(1):69–77.

    Article  CAS  PubMed  Google Scholar 

  71. Chen XL, Grey JY, Thomas S, Qiu FH, Medford RM, Wasserman MA, et al. Sphingosine kinase-1 mediates TNF-alpha-induced MCP-1 gene expression in endothelial cells: upregulation by oscillatory flow. Am J Physiol Heart Circ Physiol. 2004;287(4):H1452–8.

    Article  CAS  PubMed  Google Scholar 

  72. Guo D, Chien S, Shyy JY. Regulation of endothelial cell cycle by laminar versus oscillatory flow: distinct modes of interactions of AMP-activated protein kinase and Akt pathways. Circ Res. 2007;100(4):564–71.

    Article  CAS  PubMed  Google Scholar 

  73. Dewey CF Jr, Bussolari SR, Gimbrone MA Jr, Davies PF. The dynamic response of vascular endothelial cells to fluid shear stress. J Biomech Eng. 1981;103(3):177–85.

    Article  PubMed  Google Scholar 

  74. Remuzzi A, Dewey CF Jr, Davies PF, Gimbrone MA Jr. Orientation of endothelial cells in shear fields in vitro. Biorheology. 1984;21(4):617–30.

    Article  CAS  PubMed  Google Scholar 

  75. Go Y-M, Boo YC, Park H, Maland MC, Patel R, Pritchard KA, et al. Protein kinase B/Akt activates c-Jun NH2-terminal kinase by increasing NO production in response to shear stress. J Appl Physiol. 2001;91(4):1574–81.

    Article  CAS  PubMed  Google Scholar 

  76. Sorescu GP, Song H, Tressel SL, Hwang J, Dikalov S, Smith DA, et al. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress induces monocyte adhesion by stimulating reactive oxygen species production from a nox1-based NADPH oxidase. Circ Res. 2004;95(8):773–9.

    Article  CAS  PubMed  Google Scholar 

  77. Sorescu GP, Sykes M, Weiss D, Platt MO, Saha A, Hwang J, et al. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress stimulates an inflammatory response. J Biol Chem. 2003;278(33):31128–35.

    Article  CAS  PubMed  Google Scholar 

  78. Platt MO, Xing Y, Jo H, Yoganathan AP. Cyclic pressure and shear stress regulate matrix metalloproteinases and cathepsin activity in porcine aortic valves. J Heart Valve Dis. 2006;15(5):622–9.

    PubMed  Google Scholar 

  79. Sucosky P, Balachandran K, Elhammali A, Jo H, Yoganathan AP. 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. 2009;29(2):254–60.

    Article  CAS  PubMed  Google Scholar 

  80. Sucosky P, Padala M, Elhammali A, Balachandran K, Jo H, Yoganathan AP. Design of an ex vivo culture system to investigate the effects of shear stress on cardiovascular tissue. J Biomech Eng. 2008;130(3):035001.

    Article  PubMed  Google Scholar 

  81. Weston MW, Yoganathan AP. Biosynthetic activity in heart valve leaflets in response to in vitro flow environments. Ann Biomed Eng. 2001;29(9):752–63.

    Article  CAS  PubMed  Google Scholar 

  82. Butcher JT, Nerem RM. Valvular endothelial cells regulate the phenotype of interstitial cells in co-culture: effects of steady shear stress. Tissue Eng. 2006;12(4):905–15.

    Article  CAS  PubMed  Google Scholar 

  83. McIntosh CT, Warnock JN. Side-specific characterization of aortic valve endothelial cell adhesion molecules under cyclic strain. J Heart Valve Dis. 2013;22(5):631–9.

    PubMed  Google Scholar 

  84. Carrion K, Dyo J, Patel V, Sasik R, Mohamed SA, Hardiman G, et al. 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. 2014;9(5):e96577.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Takeda H, Komori K, Nishikimi N, Nimura Y, Sokabe M, Naruse K. Bi-phasic activation of eNOS in response to uni-axial cyclic stretch is mediated by differential mechanisms in BAECs. Life Sci. 2006;79(3):233–9.

    Article  CAS  PubMed  Google Scholar 

  86. Engelmayr GC Jr, Hildebrand DK, Sutherland FW, Mayer JE Jr, Sacks MS. A novel bioreactor for the dynamic flexural stimulation of tissue engineered heart valve biomaterials. Biomaterials. 2003;24(14):2523–32.

    Article  CAS  PubMed  Google Scholar 

  87. 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(2):175–87.

    Article  CAS  PubMed  Google Scholar 

  88. 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(5):268–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Engelmayr GC Jr, Soletti L, Vigmostad SC, Budilarto SG, Federspiel WJ, Chandran KB, et al. A novel flex-stretch-flow bioreactor for the study of engineered heart valve tissue mechanobiology. Ann Biomed Eng. 2008;36(5):700–12.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Masoumi N, Howell MC, Johnson KL, Niesslein MJ, Gerber G, Engelmayr GC Jr. Design and testing of a cyclic stretch and flexure bioreactor for evaluating engineered heart valve tissues based on poly(glycerol sebacate) scaffolds. Proc Inst Mech Eng H J Eng Med. 2014;228(6):576–86.

    Article  Google Scholar 

  91. Warnock JN, Konduri S, He Z, Yoganathan AP. Design of a sterile organ culture system for the ex vivo study of aortic heart valves. J Biomech Eng. 2005;127(5):857–61.

    Article  PubMed  Google Scholar 

  92. Durst CA, Jane Grande-Allen K. Design and physical characterization of a synchronous multivalve aortic valve culture system. Ann Biomed Eng. 2010;38(2):319–25.

    Article  PubMed  Google Scholar 

  93. Deck JD. Endothelial cell orientation on aortic valve leaflets. Cardiovasc Res. 1986;20(10):760–7.

    Article  CAS  PubMed  Google Scholar 

  94. Butcher JT, Simmons CA, Warnock JN. Mechanobiology of the aortic heart valve. J Heart Valve Dis. 2008;17(1):62–73.

    PubMed  Google Scholar 

  95. Simmons CA, Grant GR, Manduchi E, Davies PF. Spatial heterogeneity of endothelial phenotypes correlates with side-specific vulnerability to calcification in normal porcine aortic valves. Circ Res. 2005;96(7):792–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Suga S, Itoh H, Komatsu Y, Ogawa Y, Hama N, Yoshimasa T, et al. Cytokine-induced C-type natriuretic peptide (CNP) secretion from vascular endothelial cells--evidence for CNP as a novel autocrine/paracrine regulator from endothelial cells. Endocrinology. 1993;133(6):3038–41.

    Article  CAS  PubMed  Google Scholar 

  97. La M, Cao TV, Cerchiaro G, Chilton K, Hirabayashi J, Kasai K, et al. A novel biological activity for galectin-1: inhibition of leukocyte-endothelial cell interactions in experimental inflammation. Am J Pathol. 2003;163(4):1505–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Farrar EJ, Huntley GD, Butcher J. Endothelial-derived oxidative stress drives myofibroblastic activation and calcification of the aortic valve. PLoS One. 2015;10(4):e0123257.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Bosse K, Hans CP, Zhao N, Koenig SN, Huang N, Guggilam A, et al. Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease. J Mol Cell Cardiol. 2013;60:27–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. El-Hamamsy I, Balachandran K, Yacoub MH, Stevens LM, Sarathchandra P, Taylor PM, et al. Endothelium-dependent regulation of the mechanical properties of aortic valve cusps. J Am Coll Cardiol. 2009;53(16):1448–55.

    Article  CAS  PubMed  Google Scholar 

  101. Rajamannan NM, Subramaniam M, Stock SR, Stone NJ, Springett M, Ignatiev KI, et al. Atorvastatin inhibits calcification and enhances nitric oxide synthase production in the hypercholesterolaemic aortic valve. Heart. 2005;91(6):806–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Richards J, El-Hamamsy I, Chen S, Sarang Z, Sarathchandra P, Yacoub MH, et al. Side-specific endothelial-dependent regulation of aortic valve calcification: interplay of hemodynamics and nitric oxide signaling. Am J Pathol. 2013;182(5):1922–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Sun L, Sucosky P. Bone morphogenetic protein-4 and transforming growth factor-beta1 mechanisms in acute valvular response to supra-physiologic hemodynamic stresses. World J Cardiol. 2015;7(6):331–43.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Weinberg EJ, Schoen FJ, Mofrad MR. A computational model of aging and calcification in the aortic heart valve. PLoS One. 2009;4(6):e5960.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Chandra S, Rajamannan NM, Sucosky P. Computational assessment of bicuspid aortic valve wall-shear stress: implications for calcific aortic valve disease. Biomech Model Mechanobiol. 2012;11(7):1085–96.

    Article  PubMed  Google Scholar 

  106. Sun L, Rajamannan NM, Sucosky P. Defining the role of fluid shear stress in the expression of early signaling markers for calcific aortic valve disease. PLoS One. 2013;8(12):e84433.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Aikawa E, Nahrendorf M, Sosnovik D, Lok VM, Jaffer FA, Aikawa M, et al. Multimodality molecular imaging identifies proteolytic and osteogenic activities in early aortic valve disease. Circulation. 2007;115(3):377–86.

    Article  CAS  PubMed  Google Scholar 

  108. Helske S, Syvaranta S, Lindstedt KA, Lappalainen J, Oorni K, Mayranpaa MI, et al. Increased expression of elastolytic cathepsins S, K, and V and their inhibitor cystatin C in stenotic aortic valves. Arterioscler Thromb Vasc Biol. 2006;26(8):1791–8.

    Article  CAS  PubMed  Google Scholar 

  109. 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(11):1461–70.

    Article  PubMed  Google Scholar 

  110. Jian B, Narula N, Li QY, Mohler ER 3rd, Levy RJ. 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. 2003;75(2):457–65; discussion 65–6.

    Article  PubMed  Google Scholar 

  111. Mahler GJ, Frendl CM, Cao Q, Butcher JT. Effects of shear stress pattern and magnitude on mesenchymal transformation and invasion of aortic valve endothelial cells. Biotechnol Bioeng. 2014;111(11):2326–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Markwald RR, Fitzharris TP, Manasek FJ. Structural development of endocardial cushions. Am J Anat. 1977;148(1):85–119.

    Article  CAS  PubMed  Google Scholar 

  113. Markwald RR, Fitzharris TP, Smith WN. Structural analysis of endocardial cytodifferentiation. Dev Biol. 1975;42(1):160–80.

    Article  CAS  PubMed  Google Scholar 

  114. Nakajima Y, Mironov V, Yamagishi T, Nakamura H, Markwald RR. Expression of smooth muscle alpha-actin in mesenchymal cells during formation of avian endocardial cushion tissue: a role for transforming growth factor beta3. Dev Dyn. 1997;209(3):296–309.

    Article  CAS  PubMed  Google Scholar 

  115. Cote N, Mahmut A, Fournier D, Boulanger MC, Couture C, Despres JP, et al. Angiotensin receptor blockers are associated with reduced fibrosis and interleukin-6 expression in calcific aortic valve disease. Pathobiology. 2014;81(1):15–24.

    Article  CAS  PubMed  Google Scholar 

  116. Kaden JJ, Dempfle CE, Grobholz R, Fischer CS, Vocke DC, Kilic R, et al. Inflammatory regulation of extracellular matrix remodeling in calcific aortic valve stenosis. Cardiovasc Pathol. 2005;14(2):80–7.

    Article  CAS  PubMed  Google Scholar 

  117. Kaden JJ, Kilic R, Sarikoc A, Hagl S, Lang S, Hoffmann U, et al. Tumor necrosis factor alpha promotes an osteoblast-like phenotype in human aortic valve myofibroblasts: a potential regulatory mechanism of valvular calcification. Int J Mol Med. 2005;16(5):869–72.

    CAS  PubMed  Google Scholar 

  118. Mahler GJ, Farrar EJ, Butcher JT. Inflammatory cytokines promote mesenchymal transformation in embryonic and adult valve endothelial cells. Arterioscler Thromb Vasc Biol. 2013;33(1):121–30.

    Article  CAS  PubMed  Google Scholar 

  119. Guo H, Ingolia NT, Weissman JS, Bartel DP. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature. 2010;466(7308):835–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. van Rooij E, Marshall WS, Olson EN. Toward microRNA-based therapeutics for heart disease—the sense in antisense. Circ Res. 2008;103(9):919–28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Nigam V, Sievers HH, Jensen BC, Sier HA, Simpson PC, Srivastava D, et al. Altered microRNAs in bicuspid aortic valve: a comparison between stenotic and insufficient valves. J Heart Valve Dis. 2010;19(4):459–65.

    PubMed  PubMed Central  Google Scholar 

  122. Holliday CJ, Ankeny RF, Jo H, Nerem RM. Discovery of shear- and side-specific mRNAs and miRNAs in human aortic valvular endothelial cells. Am J Physiol Heart Circ Physiol. 2011;301(3):H856–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Thubrikar MJ, Aouad J, Nolan SP. Patterns of calcific deposits in operatively excised stenotic or purely regurgitant aortic valves and their relation to mechanical stress. Am J Cardiol. 1986;58(3):304–8.

    Article  CAS  PubMed  Google Scholar 

  124. Freeman RV, Otto CM. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation. 2005;111(24):3316–26.

    Article  PubMed  Google Scholar 

  125. Robicsek F, Thubrikar MJ, Fokin AA. Cause of degenerative disease of the trileaflet aortic valve: review of subject and presentation of a new theory. Ann Thorac Surg. 2002;73(4):1346–54.

    Article  PubMed  Google Scholar 

  126. Olsson M, Thyberg J, Nilsson J. Presence of oxidized low density lipoprotein in nonrheumatic stenotic aortic valves. Arterioscler Thromb Vasc Biol. 1999;19(5):1218–22.

    Article  CAS  PubMed  Google Scholar 

  127. O’Brien KD, Reichenbach DD, Marcovina SM, Kuusisto J, Alpers CE, Otto CM. Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of ‘degenerative’ valvular aortic stenosis. Arterioscler Thromb Vasc Biol. 1996;16(4):523–32.

    Article  PubMed  Google Scholar 

  128. Rajamannan NM, Subramaniam M, Rickard D, Stock SR, Donovan J, Springett M, et al. Human aortic valve calcification is associated with an osteoblast phenotype. Circulation. 2003;107(17):2181–4.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Rajamannan NM, Subramaniam M, Springett M, Sebo TC, Niekrasz M, McConnell JP, et al. Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve. Circulation. 2002;105(22):2660–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Balachandran K, Sucosky P, Jo H, Yoganathan AP. Elevated cyclic stretch alters matrix remodeling in aortic valve cusps: implications for degenerative aortic valve disease. Am J Physiol Heart Circ Physiol. 2009;296(3):H756–64.

    Article  CAS  PubMed  Google Scholar 

  131. Fujiwara K. Platelet endothelial cell adhesion molecule-1 and mechanotransduction in vascular endothelial cells. J Intern Med. 2006;259(4):373–80.

    Article  CAS  PubMed  Google Scholar 

  132. Metzler SA. The aortic valve endothelial cell: a multi-scale study of strain mechanobiology. Mississippi State: Mississippi State University; 2010.

    Google Scholar 

  133. Nakada MT, Amin K, Christofidou-Solomidou M, O'Brien CD, Sun J, Gurubhagavatula I, et al. Antibodies against the first Ig-like domain of human platelet endothelial cell adhesion molecule-1 (PECAM-1) that inhibit PECAM-1-dependent homophilic adhesion block in vivo neutrophil recruitment. J Immunol. 2000;164(1):452–62.

    Article  CAS  PubMed  Google Scholar 

  134. Vaporciyan AA, DeLisser HM, Yan HC, Mendiguren II, Thom SR, Jones ML, et al. Involvement of platelet-endothelial cell adhesion molecule-1 in neutrophil recruitment in vivo. Science. 1993;262(5139):1580–2.

    Article  CAS  PubMed  Google Scholar 

  135. Dusserre N, L’Heureux N, Bell KS, Stevens HY, Yeh J, Otte LA, et al. PECAM-1 interacts with nitric oxide synthase in human endothelial cells: implication for flow-induced nitric oxide synthase activation. Arterioscler Thromb Vasc Biol. 2004;24(10):1796–802.

    Article  CAS  PubMed  Google Scholar 

  136. Heistad DD, Wakisaka Y, Miller J, Chu Y, Pena-Silva R. Novel aspects of oxidative stress in cardiovascular diseases. Circ J. 2009;73(2):201–7.

    Article  CAS  PubMed  Google Scholar 

  137. Miller JD, Chu Y, Brooks RM, Richenbacher WE, Pena-Silva R, Heistad DD. Dysregulation of antioxidant mechanisms contributes to increased oxidative stress in calcific aortic valvular stenosis in humans. J Am Coll Cardiol. 2008;52(10):843–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. El-Hamamsy I, Chester AH, Yacoub M. Cellular regulation of the structure and function of aortic valves. J Adv Res. 2010;1(1):5–12.

    Article  Google Scholar 

  139. Chiswell BP, Zhang R, Murphy JW, Boggon TJ, Calderwood DA. The structural basis of integrin-linked kinase-PINCH interactions. Proc Natl Acad Sci U S A. 2008;105(52):20677–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Lal H, Verma SK, Foster DM, Golden HB, Reneau JC, Watson LE, et al. Integrins and proximal signaling mechanisms in cardiovascular disease. Front Biosci. 2009;14:2307–34.

    Article  CAS  Google Scholar 

  141. Legate KR, Montanez E, Kudlacek O, Fassler R. ILK, PINCH and parvin: the tIPP of integrin signalling. Nat Rev Mol Cell Biol. 2006;7(1):20–31.

    Article  CAS  PubMed  Google Scholar 

  142. Herranz B, Marquez S, Guijarro B, Aracil E, Aicart-Ramos C, Rodriguez-Crespo I, et al. Integrin-linked kinase regulates vasomotor function by preventing endothelial nitric oxide synthase uncoupling: role in atherosclerosis. Circ Res. 2012;110(3):439–49.

    Article  CAS  PubMed  Google Scholar 

  143. Critchley DR. Genetic, biochemical and structural approaches to talin function. Biochem Soc Trans. 2005;33.(Pt 6:1308–12.

    Article  CAS  PubMed  Google Scholar 

  144. Vestweber D. VE-cadherin: the major endothelial adhesion molecule controlling cellular junctions and blood vessel formation. Arterioscler Thromb Vasc Biol. 2008;28(2):223–32.

    Article  CAS  PubMed  Google Scholar 

  145. Ross R. Atherosclerosis is an inflammatory disease. Am Heart J. 1999;138(5 Pt 2):S419–20.

    Article  CAS  PubMed  Google Scholar 

  146. Balachandran K, Sucosky P, Jo H, Yoganathan AP. Elevated cyclic stretch induces aortic valve calcification in a bone morphogenic protein-dependent manner. Am J Pathol. 2010;177(1):49–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Rosenhek R, Binder T, Porenta G, Lang I, Christ G, Schemper M, et al. Predictors of outcome in severe, asymptomatic aortic stenosis. N Engl J Med. 2000;343(9):611–7.

    Article  CAS  PubMed  Google Scholar 

  148. Bach DS. Prevalence and characteristics of unoperated patients with severe aortic stenosis. J Heart Valve Dis. 2011;20(3):284–91.

    PubMed  Google Scholar 

  149. Teo KK, Corsi DJ, Tam JW, Dumesnil JG, Chan KL. Lipid lowering on progression of mild to moderate aortic stenosis: meta-analysis of the randomized placebo-controlled clinical trials on 2344 patients. Can J Cardiol. 2011;27(6):800–8.

    Article  CAS  PubMed  Google Scholar 

  150. Rosenhek R, Rader F, Loho N, Gabriel H, Heger M, Klaar U, et al. Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis. Circulation. 2004;110(10):1291–5.

    Article  CAS  PubMed  Google Scholar 

  151. O’Brien KD, Zhao XQ, Shavelle DM, Caulfield MT, Letterer RA, Kapadia SR, et al. Hemodynamic effects of the angiotensin-converting enzyme inhibitor, ramipril, in patients with mild to moderate aortic stenosis and preserved left ventricular function. J Investig Med. 2004;52(3):185–91.

    Article  PubMed  Google Scholar 

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  1. School of Chemical, Materials and Biomedical Engineering, University of Georgia, Athens, GA, USA

    James N. Warnock

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  1. The Oden Institute and the Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA

    Michael S. Sacks

  2. The Department of Bioengineering, The University of Texas at Arlington, Arlington, TX, USA

    Jun Liao

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Warnock, J.N. (2018). Endothelial Mechanotransduction. In: Sacks, M., Liao, J. (eds) Advances in Heart Valve Biomechanics. Springer, Cham. https://doi.org/10.1007/978-3-030-01993-8_2

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