Skip to main content

Advertisement

SpringerLink
Log in

Valvular Endothelial Cell Response to the Mechanical Environment—A Review

  • Review Paper
  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

A Correction to this article was published on 26 November 2021

This article has been updated

Abstract

Heart valve leaflets are complex structures containing valve endothelial cells, interstitial cells, and extracellular matrix. Heart valve endothelial cells sense mechanical stimuli, and communicate amongst themselves and the surrounding cells and extracellular matrix to maintain tissue homeostasis. In the presence of abnormal mechanical stimuli, endothelial cell communication is triggered in defense and such processes may eventually lead to cardiac disease progression. This review focuses on the role of mechanical stimuli on heart valve endothelial surfaces—from heart valve development and maintenance of tissue integrity to disease progression with related signal pathways involved in this process.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Change history

Abbreviations

VECs:

valve endothelial cells

VICs:

valve interstitial cells

EndMT:

endothelial to mesenchymal transition

ECM:

extracellular matrix

AVC:

atrioventricular canal

OFT:

outflow tract

TGF-β:

transforming growth factor-β

VEGF:

vascular endothelial growth factor

BMP:

bone morphogenetic proteins

NFATc1:

activated T-cells cytoplasmic 1

RANKL:

receptor activator of nuclear factor κΒ ligand

ERK1/2:

extracellular-regulated kinases 1 and 2

FGF4:

fibroblast growth factor 4

TNFα:

tumor necrosis factor alpha

NFκβ:

nuclear factor-kappa B

ECs:

endothelial cells

VCAM-1:

vascular cell adhesion molecule

PECAM:

platelet endothelial cell adhesion molecule

PDGF-R:

platelet-derived growth factor receptor

ICAM-3:

intercellular adhesion molecule-3

PDGF-R:

Platelet-derived growth factor and its Receptor

PI3K:

Phosphoinositide 3-kinases

FGFR3:

fibroblast growth factor receptor 3

FAK:

focal adhesion kinase

GPCRs:

G protein coupled receptors

αSMA:

alpha smooth muscle actin

NO:

nitric oxide

OPG:

osteoprotegerin

12-LOX:

12-lipoxygenase

CNP:

C-type natriuretic peptide

PTH:

parathyroid hormone

miRNA:

micro ribonucleic acid

mRNA:

messenger ribonucleic acid

eNOS:

endothelial nitric oxide synthase

klf2:

Krüppel-like Factor 2

SMAD:

small mothers against decapentaplegic

GAG:

glycosaminoglycans

AV:

aortic valve

MV:

mitral valve

PV:

pulmonary valve

TV:

tricuspid valve

TVP:

transvalvular pressure

Bmp4:

bone morphogenetic protein 4

vWF:

von Willebrand factor

ILs:

interleukins

ROS:

reactive oxygen species

Cxn43:

connexin 43

MMP:

matrix metalloproteinase

CAVD:

calcific aortic valve disease

References

  1. Mahler, G. J., Farrar, E. J., & Butcher, J. T. (2013). Inflammatory cytokines promote mesenchymal transformation in embryonic and adult valve endothelial cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 33(1), 121–130. https://doi.org/10.1161/ATVBAHA.112.300504.

    Article  CAS  PubMed  Google Scholar 

  2. Holliday, C. J., Ankeny, R. F., Jo, H., & Nerem, R. M. (2011). Discovery of shear- and side-specific mRNAs and miRNAs in human aortic valvular endothelial cells. The American Journal of Physiology-Heart and Circular Physiology, 301(3), H856–H867. https://doi.org/10.1152/ajpheart.00117.2011.

    Article  CAS  Google Scholar 

  3. Pardali E., Sanchez-Duffhues G., Gomez-Puerto M. C., Ten Dijke P. (2017). TGF-beta-Induced Endothelial-Mesenchymal Transition in Fibrotic Diseases. International Journal of Molecular Sciences. 18(10). https://doi.org/10.3390/ijms18102157.

  4. Sanchez-Duffhues, G., Garcia de Vinuesa, A., & Ten Dijke, P. (2018). Endothelial-to-mesenchymal transition in cardiovascular diseases: developmental signaling pathways gone awry. Developmental Dynamics, 247(3), 492–508. https://doi.org/10.1002/dvdy.24589.

    Article  CAS  PubMed  Google Scholar 

  5. Kovacic, J. C., Dimmeler, S., Harvey, R. P., Finkel, T., Aikawa, E., & Krenning, G., et al. (2019). Endothelial to mesenchymal transition in cardiovascular disease: JACC state-of-the-art review. Journal of the American College of Cardiology, 73(2), 190–209. https://doi.org/10.1016/j.jacc.2018.09.089.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Perez-Pomares, J. M., Gonzalez-Rosa, J. M., & Munoz-Chapuli, R. (2009). Building the vertebrate heart - an evolutionary approach to cardiac development. The International Journal Developmental Biology, 53(8-10), 1427–1443. https://doi.org/10.1387/ijdb.072409jp.

    Article  Google Scholar 

  7. Person, A. D., Klewer, S. E., & Runyan, R. B. (2005). Cell biology of cardiac cushion development. International Review of Cytology, 243, 287–335. https://doi.org/10.1016/S0074-7696(05)43005-3.

    Article  CAS  PubMed  Google Scholar 

  8. Tao, G., Kotick, J. D., & Lincoln, J. (2012). Heart valve development, maintenance, and disease: the role of endothelial cells. Current Topic in Developmental Biology, 100, 203–232. https://doi.org/10.1016/B978-0-12-387786-4.00006-3.

    Article  CAS  Google Scholar 

  9. Armstrong, E. J., & Bischoff, J. (2004). Heart valve development: endothelial cell signaling and differentiation. Circulation Research, 95(5), 459–470. https://doi.org/10.1161/01.RES.0000141146.95728.da.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Eisenberg, L. M., & Markwald, R. R. (1995). Molecular regulation of atrioventricular valvuloseptal morphogenesis. Circulation Research, 77(1), 1–6. https://doi.org/10.1161/01.res.77.1.1.

    Article  CAS  PubMed  Google Scholar 

  11. Ayoub, S., Ferrari, G., Gorman, R. C., Gorman, J. H., Schoen, F. J., & Sacks, M. S. (2016). Heart valve biomechanics and underlying mechanobiology. Comprehensive Physiology, 6(4), 1743–1780. https://doi.org/10.1002/cphy.c150048.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Butcher, J. T., & Markwald, R. R. (2007). Valvulogenesis: the moving target. Philosophical Transaction of the Royal Society London B Biological Sciences, 362(1484), 1489–1503. https://doi.org/10.1098/rstb.2007.2130.

    Article  CAS  Google Scholar 

  13. Schroeder, J. A., Jackson, L. F., Lee, D. C., & Camenisch, T. D. (2003). Form and function of developing heart valves: coordination by extracellular matrix and growth factor signaling. Journal of Molecular Medicine (Berlin), 81(7), 392–403. https://doi.org/10.1007/s00109-003-0456-5.

    Article  CAS  Google Scholar 

  14. Hinton, Jr, R. B., Lincoln, J., Deutsch, G. H., Osinska, H., Manning, P. B., & Benson, D. W., et al. (2006). Extracellular matrix remodeling and organization in developing and diseased aortic valves. Circulation Research, 98(11), 1431–1438. https://doi.org/10.1161/01.RES.0000224114.65109.4e.

    Article  CAS  PubMed  Google Scholar 

  15. Wessels, A., Markman, M. W., Vermeulen, J. L., Anderson, R. H., Moorman, A. F., & Lamers, W. H. (1996). The development of the atrioventricular junction in the human heart. Circulation Research, 78(1), 110–117. https://doi.org/10.1161/01.res.78.1.110.

    Article  CAS  PubMed  Google Scholar 

  16. Kirby, M. L., Gale, T. F., & Stewart, D. E. (1983). Neural crest cells contribute to normal aorticopulmonary septation. Science, 220(4601), 1059–1061. https://doi.org/10.1126/science.6844926.

    Article  CAS  PubMed  Google Scholar 

  17. Taber, L. A. (1998). Mechanical aspects of cardiac development. Progress in Biophysics and Molecular Biology, 69(2-3), 237–255. https://doi.org/10.1016/s0079-6107(98)00010-8.

    Article  CAS  PubMed  Google Scholar 

  18. Forouhar, A. S., Liebling, M., Hickerson, A., Nasiraei-Moghaddam, A., Tsai, H. J., & Hove, J. R., et al. (2006). The embryonic vertebrate heart tube is a dynamic suction pump. Science, 312(5774), 751–753. https://doi.org/10.1126/science.1123775.

    Article  CAS  PubMed  Google Scholar 

  19. Banjo, T., Grajcarek, J., Yoshino, D., Osada, H., Miyasaka, K. Y., & Kida, Y. S., et al. (2013). Haemodynamically dependent valvulogenesis of zebrafish heart is mediated by flow-dependent expression of miR-21. Nature Communications., 4, 1978 https://doi.org/10.1038/ncomms2978.

    Article  CAS  PubMed  Google Scholar 

  20. Wang X., Ali M. S., Lacerda C. M. R. (2018). A Three-Dimensional Collagen-Elastin Scaffold for Heart Valve Tissue Engineering. Bioengineering (Basel). 5(3). https://doi.org/10.3390/bioengineering5030069.

  21. Combs, M. D., & Yutzey, K. E. (2009). Heart valve development: regulatory networks in development and disease. Circulation Research, 105(5), 408–421. https://doi.org/10.1161/CIRCRESAHA.109.201566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. Shapero, K., Wylie-Sears, J., Levine, R. A., Mayer, Jr, J. E., & Bischoff, J. (2015). Reciprocal interactions between mitral valve endothelial and interstitial cells reduce endothelial-to-mesenchymal transition and myofibroblastic activation. Journal of Molecular and Cellular Cardiology, 80, 175–185. https://doi.org/10.1016/j.yjmcc.2015.01.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Levesque, M. J., Liepsch, D., Moravec, S., & Nerem, R. M. (1986). Correlation of endothelial cell shape and wall shear stress in a stenosed dog aorta. Arteriosclerosis, Thrombosis, and Vascular Biology, 6(2), 220–229. https://doi.org/10.1161/01.atv.6.2.220.

    Article  CAS  Google Scholar 

  25. Levesque, M. J., & Nerem, R. M. (1985). The elongation and orientation of cultured endothelial cells in response to shear stress. The Journal of Biomechanical Engineering, 107(4), 341–347. https://doi.org/10.1115/1.3138567.

    Article  CAS  PubMed  Google Scholar 

  26. Stamatas, G. N., & McIntire, L. V. (2001). Rapid flow-induced responses in endothelial cells. Biotechnology Progress, 17(3), 383–402. https://doi.org/10.1021/bp0100272.

    Article  CAS  PubMed  Google Scholar 

  27. Girard, P. R., & Nerem, R. M. (1995). Shear stress modulates endothelial cell morphology and F-actin organization through the regulation of focal adhesion-associated proteins. Journal of Cellular Physiology, 163(1), 179–193. https://doi.org/10.1002/jcp.1041630121.

    Article  CAS  PubMed  Google Scholar 

  28. Johnson, C. M., & Fass, D. N. (1983). Porcine cardiac valvular endothelial cells in culture. A relative deficiency of fibronectin synthesis in vitro. Laboratory Investigation, 49(5), 589–598.

    CAS  PubMed  Google Scholar 

  29. Farivar, R. S., Cohn, L. H., Soltesz, E. G., Mihaljevic, T., Rawn, J. D., & Byrne, J. G. (2003). Transcriptional profiling and growth kinetics of endothelium reveals differences between cells derived from porcine aorta versus aortic valve. European Journal of Cardiothoracic Surgery, 24(4), 527–534. https://doi.org/10.1016/s1010-7940(03)00408-1.

    Article  PubMed  Google Scholar 

  30. Butcher, J. T., & Nerem, R. M. (2007). Valvular endothelial cells and the mechanoregulation of valvular pathology. Philosophical Transactions of the Royal Society London B Biological Sciences, 362(1484), 1445–1457. https://doi.org/10.1098/rstb.2007.2127.

    Article  CAS  Google Scholar 

  31. Chiu, J. J., Wang, D. L., Chien, S., Skalak, R., & Usami, S. (1998). Effects of disturbed flow on endothelial cells. The Journal of Biomechanical Engineering, 120(1), 2–8. https://doi.org/10.1115/1.2834303.

    Article  CAS  PubMed  Google Scholar 

  32. Butcher, J. T., Penrod, A. M., Garcia, A. J., & Nerem, R. M. (2004). Unique morphology and focal adhesion development of valvular endothelial cells in static and fluid flow environments. Arteriosclerosis, Thrombosis, and Vascular Biology, 24(8), 1429–1434. https://doi.org/10.1161/01.ATV.0000130462.50769.5a.

    Article  CAS  PubMed  Google Scholar 

  33. Mahler, G. J., Frendl, C. M., Cao, Q., & Butcher, J. T. (2014). Effects of shear stress pattern and magnitude on mesenchymal transformation and invasion of aortic valve endothelial cells. Biotechnology and Bioengineering, 111(11), 2326–2337. https://doi.org/10.1002/bit.25291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Deck, J. D. (1986). Endothelial cell orientation on aortic valve leaflets. Cardiovascular Research, 20(10), 760–767. https://doi.org/10.1093/cvr/20.10.760.

    Article  CAS  PubMed  Google Scholar 

  35. Kilner, P. J., Yang, G. Z., Wilkes, A. J., Mohiaddin, R. H., Firmin, D. N., & Yacoub, M. H. (2000). Asymmetric redirection of flow through the heart. Nature, 404(6779), 759–761. https://doi.org/10.1038/35008075.

    Article  CAS  PubMed  Google Scholar 

  36. Brooks, A. R., Lelkes, P. I., & Rubanyi, G. M. (2002). Gene expression profiling of human aortic endothelial cells exposed to disturbed flow and steady laminar flow. Physiological Genomics, 9(1), 27–41. https://doi.org/10.1152/physiolgenomics.00075.2001.

    Article  CAS  PubMed  Google Scholar 

  37. Mohler, III, E. R., Gannon, F., Reynolds, C., Zimmerman, R., Keane, M. G., & Kaplan, F. S. (2001). Bone formation and inflammation in cardiac valves. Circulation, 103(11), 1522–1528. https://doi.org/10.1161/01.cir.103.11.1522.

    Article  PubMed  Google Scholar 

  38. Brewer, R. J., Mentzer, Jr, R. M., Deck, J. D., Ritter, R. C., Trefil, J. S., & Nolan, S. P. (1977). An in vivo study of the dimensional changes of the aortic valve leaflets during the cardiac cycle. The Journal of Thoracic Cardiovascular Surgery, 74(4), 645–650.

    Article  CAS  Google Scholar 

  39. Bischoff, J., & Aikawa, E. (2011). Progenitor cells confer plasticity to cardiac valve endothelium. Journal of Cardiovascular Translation Research, 4(6), 710–719. https://doi.org/10.1007/s12265-011-9312-0.

    Article  Google Scholar 

  40. Garside, V. C., Chang, A. C., Karsan, A., & Hoodless, P. A. (2013). Co-ordinating Notch, BMP, and TGF-beta signaling during heart valve development. Cellular and Molecular Life Science, 70(16), 2899–2917. https://doi.org/10.1007/s00018-012-1197-9.

    Article  CAS  Google Scholar 

  41. Johnson, E. N., Lee, Y. M., Sander, T. L., Rabkin, E., Schoen, F. J., & Kaushal, S., et al. (2003). NFATc1 mediates vascular endothelial growth factor-induced proliferation of human pulmonary valve endothelial cells. The Journal of Biology Chemistry, 278(3), 1686–1692. https://doi.org/10.1074/jbc.M210250200.

    Article  CAS  Google Scholar 

  42. Farrar, E. J., & Butcher, J. T. (2014). Heterogeneous susceptibility of valve endothelial cells to mesenchymal transformation in response to TNFalpha. Annals of Biomedical Engineering, 42(1), 149–161. https://doi.org/10.1007/s10439-013-0894-3.

    Article  PubMed  Google Scholar 

  43. Zhong, A., Mirzaei, Z., & Simmons, C. A. (2018). The roles of matrix stiffness and ss-catenin signaling in endothelial-to-mesenchymal transition of aortic valve endothelial cells. Cardiovascular Engineering and Technology, 9(2), 158–167. https://doi.org/10.1007/s13239-018-0363-0.

    Article  PubMed  Google Scholar 

  44. Dahal, S., Huang, P., Murray, B. T., & Mahler, G. J. (2017). Endothelial to mesenchymal transformation is induced by altered extracellular matrix in aortic valve endothelial cells. Journal of Biomedical Materials Research Part A, 105(10), 2729–2741. https://doi.org/10.1002/jbm.a.36133.

    Article  CAS  PubMed  Google Scholar 

  45. Tompkins, R. G., Schnitzer, J. J., & Yarmush, M. L. (1989). Macromolecular transport within heart valves. Circulation Research, 64(6), 1213–1223. https://doi.org/10.1161/01.res.64.6.1213.

    Article  CAS  PubMed  Google Scholar 

  46. Christie, G. W. (1992). Anatomy of aortic heart valve leaflets: the influence of glutaraldehyde fixation on function. European Journal of Cardiothoracic Surgical, 6, S25–S32. Suppl 1discussion S3.

    Article  Google Scholar 

  47. Liu, A. C., Joag, V. R., & Gotlieb, A. I. (2007). The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology. The American Journal of Pathology, 171(5), 1407–1418. https://doi.org/10.2353/ajpath.2007.070251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Leask, R. L., Jain, N., & Butany, J. (2003). Endothelium and valvular diseases of the heart. Microscopy Research and Technique, 60(2), 129–137. https://doi.org/10.1002/jemt.10251.

    Article  PubMed  Google Scholar 

  49. Gould, S. T., Matherly, E. E., Smith, J. N., Heistad, D. D., & Anseth, K. S. (2014). The role of valvular endothelial cell paracrine signaling and matrix elasticity on valvular interstitial cell activation. Biomaterials, 35(11), 3596–3606. https://doi.org/10.1016/j.biomaterials.2014.01.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Richards, J., El-Hamamsy, I., Chen, S., Sarang, Z., Sarathchandra, P., & Yacoub, M. H., et al. (2013). Side-specific endothelial-dependent regulation of aortic valve calcification: interplay of hemodynamics and nitric oxide signaling. The American Journal of Pathology, 182(5), 1922–1931. https://doi.org/10.1016/j.ajpath.2013.01.037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Simmons, C. A., Grant, G. R., Manduchi, E., & Davies, P. F. (2005). Spatial heterogeneity of endothelial phenotypes correlates with side-specific vulnerability to calcification in normal porcine aortic valves. Circulation Research, 96(7), 792–799. https://doi.org/10.1161/01.RES.0000161998.92009.64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Jono, S., Nishizawa, Y., Shioi, A., & Morii, H. (1998). 1,25-Dihydroxyvitamin D3 increases in vitro vascular calcification by modulating secretion of endogenous parathyroid hormone-related peptide. Circulation, 98(13), 1302–1306. https://doi.org/10.1161/01.cir.98.13.1302.

    Article  CAS  PubMed  Google Scholar 

  53. Huang, Z., Li, J., Jiang, Z., Qi, Y., Tang, C., & Du, J. (2003). Effects of adrenomedullin, C-type natriuretic peptide, and parathyroid hormone-related peptide on calcification in cultured rat vascular smooth muscle cells. Journal of Cardiovascular Pharmacology, 42(1), 89–97. https://doi.org/10.1097/00005344-200307000-00014.

    Article  CAS  PubMed  Google Scholar 

  54. Xu, S., Liu, A. C., & Gotlieb, A. I. (2010). Common pathogenic features of atherosclerosis and calcific aortic stenosis: role of transforming growth factor-beta. Cardiovascular Pathology, 19(4), 236–247. https://doi.org/10.1016/j.carpath.2009.09.007.

    Article  CAS  PubMed  Google Scholar 

  55. Guerraty M. A., Grant G. R., Karanian J. W., Chiesa O. A., Pritchard W. F., Davies P. F. (2011). Side-specific expression of activated leukocyte adhesion molecule (ALCAM; CD166) in pathosusceptible regions of swine aortic valve endothelium. The Journal of Heart Valve Disease, 20(2):165–167.

  56. Dvorin, E. L., Jacobson, J., Roth, S. J., & Bischoff, J. (2003). Human pulmonary valve endothelial cells express functional adhesion molecules for leukocytes. The Journal of Heart Valve Disease, 12(5), 617–624.

    PubMed  PubMed Central  Google Scholar 

  57. Rathan, S., Ankeny, C. J., Arjunon, S., Ferdous, Z., Kumar, S., & Fernandez Esmerats, J., et al. (2016). Identification of side- and shear-dependent microRNAs regulating porcine aortic valve pathogenesis. Scientific Reports, 6, 25397 https://doi.org/10.1038/srep25397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Miragoli, M., Yacoub, M. H., El-Hamamsy, I., Sanchez-Alonso, J. L., Moshkov, A., & Mongkoldhumrongkul, N., et al. (2014). Side-specific mechanical properties of valve endothelial cells. The American Journal of Physiology-Heart and Circulatory Physiology, 307(1), H15–H24. https://doi.org/10.1152/ajpheart.00228.2013.

    Article  CAS  PubMed  Google Scholar 

  59. Otto, C. M., Kuusisto, J., Reichenbach, D. D., Gown, A. M., & O’Brien, K. D. (1994). Characterization of the early lesion of ‘degenerative’ valvular aortic stenosis. Histological and immunohistochemical studies. Circulation, 90(2), 844–853. https://doi.org/10.1161/01.cir.90.2.844.

    Article  CAS  PubMed  Google Scholar 

  60. Weinberg, E. J., Mack, P. J., Schoen, F. J., Garcia-Cardena, G., & Kaazempur Mofrad, M. R. (2010). Hemodynamic environments from opposing sides of human aortic valve leaflets evoke distinct endothelial phenotypes in vitro. Cardiovascular Engineering, 10 (1), 5 –11. https://doi.org/10.1007/s10558-009-9089-9.

    Article  PubMed  Google Scholar 

  61. Butcher, J. T., & Nerem, R. M. (2006). Valvular endothelial cells regulate the phenotype of interstitial cells in co-culture: effects of steady shear stress. Tissue Engineering, 12(4), 905–915. https://doi.org/10.1089/ten.2006.12.905.

    Article  CAS  PubMed  Google Scholar 

  62. Butcher, J. T., 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. Arteriosclerosis, Thrombosis, and Vascular Biology, 26(1), 69–77. https://doi.org/10.1161/01.ATV.0000196624.70507.0d.

    Article  CAS  PubMed  Google Scholar 

  63. Ankeny, R. F., Thourani, V. H., Weiss, D., Vega, J. D., Taylor, W. R., & Nerem, R. M., et al. (2011). Preferential activation of SMAD1/5/8 on the fibrosa endothelium in calcified human aortic valves–association with low BMP antagonists and SMAD6. PLoS One, 6(6), e20969 https://doi.org/10.1371/journal.pone.0020969.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Mongkoldhumrongkul, N., Latif, N., Yacoub, M. H., & Chester, A. H. (2018). Effect of side-specific valvular shear stress on the content of extracellular matrix in aortic valves. Cardiovascular Engineering and Technology, 9(2), 151–157. https://doi.org/10.1007/s13239-016-0280-z.

    Article  PubMed  Google Scholar 

  65. Sacks, M. S., & Yoganathan, A. P. (2007). Heart valve function: a biomechanical perspective. Philosophical Transactions of the Royal Society London B Biological Sciences, 362(1484), 1369–1391. https://doi.org/10.1098/rstb.2007.2122.

    Article  Google Scholar 

  66. Guyton A. C. (1976). Textbook of Medical Physiology: Saunders.

  67. Yap, C. H., Saikrishnan, N., Tamilselvan, G., & Yoganathan, A. P. (2012). Experimental measurement of dynamic fluid shear stress on the aortic surface of the aortic valve leaflet. Biomechanics and Modeling Mechanobiology, 11(1-2), 171–182. https://doi.org/10.1007/s10237-011-0301-7.

    Article  Google Scholar 

  68. Steed, E., Boselli, F., & Vermot, J. (2016). Hemodynamics driven cardiac valve morphogenesis. Biochimica et Biophysica Acta, 1863(7 Pt B), 1760–1766. https://doi.org/10.1016/j.bbamcr.2015.11.014.

    Article  CAS  Google Scholar 

  69. Boselli, F., Freund, J. B., & Vermot, J. (2015). Blood flow mechanics in cardiovascular development. Cellular and Molecular Life Sciences, 72(13), 2545–2559. https://doi.org/10.1007/s00018-015-1885-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Vermot, J., Forouhar, A. S., 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), e1000246 https://doi.org/10.1371/journal.pbio.1000246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 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. Current Biology, 25(10), 1354–1361. https://doi.org/10.1016/j.cub.2015.03.038.

    Article  CAS  PubMed  Google Scholar 

  72. Vesely, I., & Noseworthy, R. (1992). Micromechanics of the fibrosa and the ventricularis in aortic valve leaflets. The Journal of Biomechanics, 25(1), 101–113. https://doi.org/10.1016/0021-9290(92)90249-z.

    Article  CAS  PubMed  Google Scholar 

  73. Nakajima, Y., Yamagishi, T., Hokari, S., & Nakamura, H. (2000). Mechanisms involved in valvuloseptal endocardial cushion formation in early cardiogenesis: roles of transforming growth factor (TGF)-beta and bone morphogenetic protein (BMP). The Anatomical Record, 258(2), 119–127.

    Article  CAS  Google Scholar 

  74. Yap, C. H., Saikrishnan, N., & Yoganathan, A. P. (2012). Experimental measurement of dynamic fluid shear stress on the ventricular surface of the aortic valve leaflet. Biomechanics and Modeling in Mechanobiology, 11(1-2), 231–44. https://doi.org/10.1007/s10237-011-0306-2.

    Article  PubMed  Google Scholar 

  75. Durbin, A. D., & Gotlieb, A. I. (2002). Advances towards understanding heart valve response to injury. Cardiovascular Pathology, 11(2), 69–77. https://doi.org/10.1016/s1054-8807(01)00109-0.

    Article  PubMed  Google Scholar 

  76. Bosse, K., Hans, C. P., Zhao, N., Koenig, S. N., Huang, N., & Guggilam, A., et al. (2013). Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease. Journal of Molecular and Cellular Cardiology, 60, 27–35. https://doi.org/10.1016/j.yjmcc.2013.04.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Nicoli, S., Standley, C., Walker, P., Hurlstone, A., Fogarty, K. E., & Lawson, N. D. (2010). MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis. Nature, 464(7292), 1196–1200. https://doi.org/10.1038/nature08889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Thubrikar, M. J., Aouad, J., & Nolan, S. P. (1986). Comparison of the in vivo and in vitro mechanical properties of aortic valve leaflets. The Journal of Thoracic and Cardiovascular Surgery, 92(1), 29–36.

    Article  CAS  Google Scholar 

  79. Metzler, S. A., Pregonero, C. A., Butcher, J. T., Burgess, S. C., & Warnock, J. N. (2008). Cyclic strain regulates pro-inflammatory protein expression in porcine aortic valve endothelial cells. The Journal of Heart Valve Disease, 17(5), 571–577.

    PubMed  Google Scholar 

  80. Balachandran, K., Sucosky, P., Jo, H., & Yoganathan, A. P. (2009). Elevated cyclic stretch alters matrix remodeling in aortic valve cusps: implications for degenerative aortic valve disease. The American Journal of Physiology-Heart and Circulatory Physiology, 296(3), H756–H764.

    Article  CAS  Google Scholar 

  81. Smith, D. B., Sacks, M. S., Vorp, D. A., & Thornton, M. (2000). Surface geometric analysis of anatomic structures using biquintic finite element interpolation. Annual Review of Biomedical Engineering, 28(6), 598–611. https://doi.org/10.1114/1.1306342.

    Article  CAS  Google Scholar 

  82. Balachandran, K., Alford, P. W., Wylie-Sears, J., Goss, J. A., Grosberg, A., & Bischoff, J., et al. (2011). Cyclic strain induces dual-mode endothelial-mesenchymal transformation of the cardiac valve. Proceedings of the National Academy of Sciences of the United States of America, 108(50), 19943–19948. https://doi.org/10.1073/pnas.1106954108.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Young, E. W., Wheeler, A. R., & Simmons, C. A. (2007). Matrix-dependent adhesion of vascular and valvular endothelial cells in microfluidic channels. Lab on a Chip, 7(12), 1759–1766. https://doi.org/10.1039/b712486d.

    Article  CAS  PubMed  Google Scholar 

  84. Sucosky, P., Balachandran, K., Elhammali, A., Jo, H., & Yoganathan, A. P. (2009). Altered shear stress stimulates upregulation of endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-beta1-dependent pathway. Arteriosclerosis, Thrombosis, and Vascular Biology, 29(2), 254–260. https://doi.org/10.1161/ATVBAHA.108.176347.

    Article  CAS  PubMed  Google Scholar 

  85. Metzler, S. A., Digesu, C. S., Howard, J. I., Filip To, S. D., & Warnock, J. N. (2012). Live en face imaging of aortic valve leaflets under mechanical stress. Biomechanics and Modeling in Mechanobiology, 11(3-4), 355–361. https://doi.org/10.1007/s10237-011-0315-1.

    Article  PubMed  Google Scholar 

  86. Lo, D., & Vesely, I. (1995). Biaxial strain analysis of the porcine aortic valve. The Annals of Thoracic Surgery, 60(2 Suppl), S374–S378. https://doi.org/10.1016/0003-4975(95)00249-k.

    Article  CAS  PubMed  Google Scholar 

  87. Adamczyk, M. M., & Vesely, I. (2002). Characteristics of compressive strains in porcine aortic valves cusps. The Journal of Heart Valve Disease, 11(1), 75–83.

    PubMed  Google Scholar 

  88. Anstine, L. J., Bobba, C., Ghadiali, S., & Lincoln, J. (2016). Growth and maturation of heart valves leads to changes in endothelial cell distribution, impaired function, decreased metabolism and reduced cell proliferation. Journal of Molecular and Cellular Cardiology, 100, 72–82. https://doi.org/10.1016/j.yjmcc.2016.10.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. McIntosh, C. T., & Warnock, J. N. (2013). Side-specific characterization of aortic valve endothelial cell adhesion molecules under cyclic strain. The Journal of Heart Valve Disease, 22(5), 631–639.

    PubMed  Google Scholar 

  90. Chen, J. H., & Simmons, C. A. (2011). Cell-matrix interactions in the pathobiology of calcific aortic valve disease: critical roles for matricellular, matricrine, and matrix mechanics cues. Circulation Research, 108(12), 1510–1524. https://doi.org/10.1161/CIRCRESAHA.110.234237.

    Article  CAS  PubMed  Google Scholar 

  91. Zhao, R., Sider, K. L., & Simmons, C. A. (2011). Measurement of layer-specific mechanical properties in multilayered biomaterials by micropipette aspiration. Acta Biomaterialia, 7(3), 1220–1227. https://doi.org/10.1016/j.actbio.2010.11.004.

    Article  CAS  PubMed  Google Scholar 

  92. Sahasakul, Y., Edwards, W. D., Naessens, J. M., & Tajik, A. J. (1988). Age-related changes in aortic and mitral valve thickness: implications for two-dimensional echocardiography based on an autopsy study of 200 normal human hearts. The American Journal of Cardiology, 62(7), 424–430. https://doi.org/10.1016/0002-9149(88)90971-x.

    Article  CAS  PubMed  Google Scholar 

  93. Edwards, M. B., Draper, E. R., Hand, J. W., Taylor, K. M., & Young, I. R. (2005). Mechanical testing of human cardiac tissue: some implications for MRI safety. Journal of Cardiovascular Magnetic Resonance, 7(5), 835–840. https://doi.org/10.1080/10976640500288149.

    Article  PubMed  Google Scholar 

  94. Lee, J., Estlack, Z., Somaweera, H., Wang, X., Lacerda, C. M. R., & Kim, J. (2018). A microfluidic cardiac flow profile generator for studying the effect of shear stress on valvular endothelial cells. Lab on a Chip, 18(19), 2946–2954. https://doi.org/10.1039/c8lc00545a.

    Article  CAS  PubMed  Google Scholar 

  95. Daniel Hoehn, L. S., & Philippe, S. (2010). Role of pathologic shear stress alterations in aortic valve endothelial activation. Cardiovascular Engineering and Technology, 1, 165–178. 2010;1:165–78.

    Article  Google Scholar 

  96. Metzler, S. A., Waller, S. C., & Warnock, J. N. (2019). Quantitative characterization of aortic valve endothelial cell viability and morphology in situ under cyclic stretch. Cardiovascular Engineering and Technology, 10(1), 173–180. https://doi.org/10.1007/s13239-018-00375-1.

    Article  PubMed  Google Scholar 

  97. Balachandran, K., Konduri, S., Sucosky, P., Jo, H., & Yoganathan, A. P. (2006). An ex vivo study of the biological properties of porcine aortic valves in response to circumferential cyclic stretch. Annual Review of Biomedical Engineering, 34(11), 1655–1665. https://doi.org/10.1007/s10439-006-9167-8.

    Article  Google Scholar 

  98. Mylonakis, E., & Calderwood, S. B. (2001). Infective endocarditis in adults. The New England Journal of Medicine, 345(18), 1318–1330. https://doi.org/10.1056/NEJMra010082.

    Article  CAS  PubMed  Google Scholar 

  99. Leopold, J. A. (2012). Cellular mechanisms of aortic valve calcification. Circulation Cardiovascular Interventions, 5(4), 605–614. https://doi.org/10.1161/CIRCINTERVENTIONS.112.971028.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Isoda, K., Matsuki, T., Kondo, H., Iwakura, Y., & Ohsuzu, F. (2010). Deficiency of interleukin-1 receptor antagonist induces aortic valve disease in BALB/c mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 30(4), 708–715. https://doi.org/10.1161/ATVBAHA.109.201749.

    Article  CAS  PubMed  Google Scholar 

  101. Hsieh, H. J., Liu, C. A., Huang, B., Tseng, A. H., & Wang, D. L. (2014). Shear-induced endothelial mechanotransduction: the interplay between reactive oxygen species (ROS) and nitric oxide (NO) and the pathophysiological implications. Journal of Biomedical Science, 21, 3 https://doi.org/10.1186/1423-0127-21-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Otto, C. M., Lind, B. K., Kitzman, D. W., Gersh, B. J., & Siscovick, D. S. (1999). Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. The New England Journal of Medicine, 341(3), 142–147. https://doi.org/10.1056/NEJM199907153410302.

    Article  Google Scholar 

  103. Mohler, III, E. R. (2000). Are atherosclerotic processes involved in aortic-valve calcification? Lancet, 356(9229), 524–525. https://doi.org/10.1016/S0140-6736(00)02572-1.

    Article  PubMed  Google Scholar 

  104. Poggio P., Cavallotti L., Songia P., Di Minno A., Ambrosino P., Mammana L., et al. (2016). Impact of valve morphology on the prevalence of coronary artery disease: a systematic review and meta-analysis. Journal of the American Heart Association, 5(5). https://doi.org/10.1161/JAHA.116.003200.

  105. Jackson, V., Eriksson, M. J., Caidahl, K., Eriksson, P., & Franco-Cereceda, A. (2014). Ascending aortic dilatation is rarely associated with coronary artery disease regardless of aortic valve morphology. The Journal of Thoracic and Cardiovascular Surgery, 148(6), 2973–80 e1. https://doi.org/10.1016/j.jtcvs.2014.08.023.

    Article  PubMed  Google Scholar 

  106. Davies, M. J., Treasure, T., & Parker, D. J. (1996). Demographic characteristics of patients undergoing aortic valve replacement for stenosis: relation to valve morphology. Heart, 75(2), 174–178. https://doi.org/10.1136/hrt.75.2.174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Otto, C. M. (2002). Calcification of bicuspid aortic valves. Heart, 88(4), 321–322. https://doi.org/10.1136/heart.88.4.321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Boudoulas, K. D., Wolfe, B., Ravi, Y., Lilly, S., Nagaraja, H. N., & Sai-Sudhakar, C. B. (2015). The aortic stenosis complex: aortic valve, atherosclerosis, aortopathy. Journal of Cardiology, 65(5), 377–382. https://doi.org/10.1016/j.jjcc.2014.12.021.

    Article  PubMed  Google Scholar 

  109. O’Brien, K. D., Reichenbach, D. D., Marcovina, S. M., Kuusisto, J., Alpers, C. E., & Otto, C. M. (1996). Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of ‘degenerative’ valvular aortic stenosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 16(4), 523–532. https://doi.org/10.1161/01.atv.16.4.523.

    Article  PubMed  Google Scholar 

  110. Olsson, M., Thyberg, J., & Nilsson, J. (1999). Presence of oxidized low density lipoprotein in nonrheumatic stenotic aortic valves. Arteriosclerosis, Thrombosis, and Vascular Biology, 19(5), 1218–1222. https://doi.org/10.1161/01.atv.19.5.1218.

    Article  CAS  PubMed  Google Scholar 

  111. O’Brien, K. D., Kuusisto, J., Reichenbach, D. D., Ferguson, M., Giachelli, C., & Alpers, C. E., et al. (1995). Osteopontin is expressed in human aortic valvular lesions. Circulation, 92(8), 2163–2168. https://doi.org/10.1161/01.cir.92.8.2163.

    Article  PubMed  Google Scholar 

  112. Rajamannan, N. M., Subramaniam, M., Rickard, D., Stock, S. R., Donovan, J., & Springett, M., et al. (2003). Human aortic valve calcification is associated with an osteoblast phenotype. Circulation, 107(17), 2181–2184. https://doi.org/10.1161/01.CIR.0000070591.21548.69.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Speer, M. Y., & Giachelli, C. M. (2004). Regulation of cardiovascular calcification. Cardiovascular Pathology, 13(2), 63–70. https://doi.org/10.1016/S1054-8807(03)00130-3.

    Article  CAS  PubMed  Google Scholar 

  114. Schinke, T., McKee, M. D., & Karsenty, G. (1999). Extracellular matrix calcification: where is the action? Nature Genetics, 21(2), 150–151. https://doi.org/10.1038/5928.

    Article  CAS  PubMed  Google Scholar 

  115. Bucay, N., Sarosi, I., Dunstan, C. R., Morony, S., Tarpley, J., & Capparelli, C., et al. (1998). osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes and Development, 12(9), 1260–1268. https://doi.org/10.1101/gad.12.9.1260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Mohler, III, E. R., Chawla, M. K., Chang, A. W., Vyavahare, N., Levy, R. J., & Graham, L., et al. (1999). Identification and characterization of calcifying valve cells from human and canine aortic valves. The Journal of Heart Valve Disease, 8(3), 254–260.

    PubMed  Google Scholar 

  117. Tintut, Y., Patel, J., Territo, M., Saini, T., Parhami, F., & Demer, L. L. (2002). Monocyte/macrophage regulation of vascular calcification in vitro. Circulation, 105(5), 650–655. https://doi.org/10.1161/hc0502.102969.

    Article  CAS  PubMed  Google Scholar 

  118. Mody, N., Parhami, F., Sarafian, T. A., & Demer, L. L. (2001). Oxidative stress modulates osteoblastic differentiation of vascular and bone cells. Free Radical Biology and Medicine, 31(4), 509–519. https://doi.org/10.1016/s0891-5849(01)00610-4.

    Article  CAS  PubMed  Google Scholar 

  119. Kaden, J. J., Bickelhaupt, S., Grobholz, R., Haase, K. K., Sarikoc, A., & Kilic, R., et al. (2004). Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulate aortic valve calcification. Journal of Molecular and Cellular Cardiology, 36(1), 57–66. https://doi.org/10.1016/j.yjmcc.2003.09.015.

    Article  CAS  PubMed  Google Scholar 

  120. 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), e48843 https://doi.org/10.1371/journal.pone.0048843.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Aicher, D., Urbich, C., Zeiher, A., Dimmeler, S., & Schafers, H. J. (2007). Endothelial nitric oxide synthase in bicuspid aortic valve disease. The Annals of Thoracic Surgery, 83(4), 1290–1294. https://doi.org/10.1016/j.athoracsur.2006.11.086.

    Article  PubMed  Google Scholar 

  122. Lin, C. J., Lin, C. Y., Chen, C. H., Zhou, B., & Chang, C. P. (2012). Partitioning the heart: mechanisms of cardiac septation and valve development. Development, 139(18), 3277–3299. https://doi.org/10.1242/dev.063495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Fernandez Esmerats, J., Heath, J., & Jo, H. (2016). Shear-sensitive genes in aortic valve endothelium. Antioxidants and Redox Signaling, 25(7), 401–414.

    Article  CAS  Google Scholar 

  124. Weston, M. W., LaBorde, D. V., & Yoganathan, A. P. (1999). Estimation of the shear stress on the surface of an aortic valve leaflet. Annual Review of Biomedical Engineering, 27(4), 572–579. https://doi.org/10.1114/1.199.

    Article  CAS  Google Scholar 

  125. Wedding, K. L., Draney, M. T., Herfkens, R. J., Zarins, C. K., Taylor, C. A., & Pelc, N. J. (2002). Measurement of vessel wall strain using cine phase contrast MRI. Journal of Magnetic Resonance Imaging, 15(4), 418–428. https://doi.org/10.1002/jmri.10077.

    Article  PubMed  Google Scholar 

  126. Draney, M. T., Herfkens, R. J., Hughes, T. J., Pelc, N. J., Wedding, K. L., & Zarins, C. K., et al. (2002). Quantification of vessel wall cyclic strain using cine phase contrast magnetic resonance imaging. Annual Review of Biomedical Engineering, 30(8), 1033–1045. https://doi.org/10.1114/1.1513566.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by startup funds provided to C.M.R.L. by Texas Tech University.

Author contributions

N.D. drafted, edited, and revised the manuscript. C.M.R.L. conceptualized, provided scientific input, edited and revised manuscript. All authors have read and approved the final manuscript.

Author information

Authors and Affiliations

  1. Jasper Department of Chemical Engineering, The University of Texas at Tyler, 3900 University Blvd, Tyler, 75799, TX, US

    Nandini Deb Ph.D. & Carla M. R. Lacerda Ph.D.

Authors
  1. Nandini Deb Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carla M. R. Lacerda Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carla M. R. Lacerda Ph.D..

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Deb, N., Lacerda, C.M.R. Valvular Endothelial Cell Response to the Mechanical Environment—A Review. Cell Biochem Biophys 79, 695–709 (2021). https://doi.org/10.1007/s12013-021-01039-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12013-021-01039-z

Keywords

Search

Navigation