Skip to main content

Advertisement

SpringerLink
Log in

Progenitor Cells Confer Plasticity to Cardiac Valve Endothelium

  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

The endothelium covering the aortic, pulmonary, mitral, and tricuspid valves looks much like the endothelium throughout the vasculature, in terms of general morphology and expression of many endothelial markers. Closer examination, however, reveals important differences and hints of a unique phenotype that reflects the valvular endothelium's embryonic history, and potentially, its ability to maintain integrity and function over a life span of dynamic mechanical stress. A well-studied property that sets the cardiac valvular endothelium apart is the ability to transition from an endothelial to a mesenchymal phenotype—an event known as epithelial to mesenchymal transition (EMT). EMT is a critical step during embryonic valvulogenesis, it can occur in post-natal valves and has recently been implicated in the adaptive response of mitral valve leaflets exposed to a controlled in vivo setting designed to mimic the leaflet tethering that occurs in ischemic mitral regurgitation. In this review, we will discuss what is known about valvular endothelial cells, with a particular focus on post-natal, adult valves. We will put forth the idea that at subset of valvular endothelial cells are progenitor cells, which may serve to replenish valvular cells during normal cellular turnover and in response to injury and disease.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Lincoln, J., Alfieri, C. M., & Yutzey, K. E. (2004). Development of heart valve leaflets and supporting apparatus in chicken and mouse embryos. Developmental Dynamics, 230, 239–250.

    Article  PubMed  CAS  Google Scholar 

  2. de Lange, F. J., Moorman, A. F., Anderson, R. H., Manner, J., Soufan, A. T., de Gier-de Vries, C., et al. (2004). Lineage and morphogenetic analysis of the cardiac valves. Circulation Research, 95, 645–654.

    Article  PubMed  Google Scholar 

  3. Liu, A. C., Joag, V. R., & Gotlieb, A. I. (2007). The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology. American Journal of Pathology, 171, 1407–1418.

    Article  PubMed  CAS  Google Scholar 

  4. Maron, B. J., & Hutchins, G. M. (1974). The development of the semilunar valves in the human heart. American Journal of Pathology, 74, 331–344.

    PubMed  CAS  Google Scholar 

  5. Hurle, J. M. (1979). Scanning and light microscope studies of the development of the chick embryo semilunar heart valves. Anatomy and Embryology, 157, 69–80.

    Article  PubMed  CAS  Google Scholar 

  6. Hurle, J. M., Colvee, E., & Blanco, A. M. (1980). Development of mouse semilunar valves. Anatomy and Embryology, 160, 83–91.

    Article  PubMed  CAS  Google Scholar 

  7. Hurle, J. M., & Colvee, E. (1983). Changes in the endothelial morphology of the developing semilunar heart valves. A tem and sem study in the chick. Anatomy and Embryology, 167, 67–83.

    Article  PubMed  CAS  Google Scholar 

  8. Deck, J. D. (1986). Endothelial cell orientation on aortic valve leaflets. Cardiovascular Research, 20, 760–767.

    Article  PubMed  CAS  Google Scholar 

  9. 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, 1429–1434.

    Article  PubMed  CAS  Google Scholar 

  10. 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, 792–799.

    Article  PubMed  CAS  Google Scholar 

  11. 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, 69–77.

    Article  PubMed  CAS  Google Scholar 

  12. Guerraty, M. A., Grant, G. R., Karanian, J. W., Chiesa, O. A., Pritchard, W. F., & Davies, P. F. (2010). Hypercholesterolemia induces side-specific phenotypic changes and peroxisome proliferator-activated receptor-gamma pathway activation in swine aortic valve endothelium. Arteriosclerosis, Thrombosis, and Vascular Biology, 30, 225–231.

    Article  PubMed  CAS  Google Scholar 

  13. 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, 254–260.

    Article  PubMed  CAS  Google Scholar 

  14. Aikawa, E., Whittaker, P., Farber, M., Mendelson, K., Padera, R. F., 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, 1344–1352.

    Article  PubMed  Google Scholar 

  15. Chi, J. T., Chang, H. Y., Haraldsen, G., Jahnsen, F. L., Troyanskaya, O. G., Chang, D. S., et al. (2003). Endothelial cell diversity revealed by global expression profiling. Proceedings of the National Academy of Sciences of the United States of America, 100, 10623–10628.

    Article  PubMed  CAS  Google Scholar 

  16. 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, 589–598.

    PubMed  CAS  Google Scholar 

  17. Johnson, C. M., & Helgeson, S. C. (1993). Fibronectin biosynthesis and cell-surface expression by cardiac and non-cardiac endothelial cells. American Journal of Pathology, 142, 1401–1408.

    PubMed  CAS  Google Scholar 

  18. Simon, A., Zavazava, N., Sievers, H. H., & Muller-Ruchholtz, W. (1993). In vitro cultivation and immunogenicity of human cardiac valve endothelium. Journal of Cardiac Surgery, 8, 656–665.

    Article  PubMed  CAS  Google Scholar 

  19. Markwald, R. R., Fitzharris, T. P., & Manasek, F. J. (1977). Structural development of endocardial cushions. The American Journal of Anatomy, 148, 85–119.

    Article  PubMed  CAS  Google Scholar 

  20. Markwald, R. R., Fitzharris, T. P., & Smith, W. N. (1975). Structural analysis of endocardial cytodifferentiation. Developmental Biology, 42, 160–180.

    Article  PubMed  CAS  Google Scholar 

  21. Krug, E. L., Runyan, R. B., & Markwald, R. R. (1985). Protein extracts from early embryonic hearts initiate cardiac endothelial cytodifferentiation. Developmental Biology, 112, 414–426.

    Article  PubMed  CAS  Google Scholar 

  22. Markwald, R., Eisenberg, C., Eisenberg, L., Trusk, T., & Sugi, Y. (1996). Epithelial-mesenchymal transformations in early avian heart development. Acta Anatomica, 156, 173–186.

    Article  PubMed  CAS  Google Scholar 

  23. Sugi, Y., Yamamura, H., Okagawa, H., & Markwald, R. R. (2004). Bone morphogenetic protein-2 can mediate myocardial regulation of atrioventricular cushion mesenchymal cell formation in mice. Developmental Biology, 269, 505–518.

    Article  PubMed  CAS  Google Scholar 

  24. Ma, L., Lu, M. F., Schwartz, R. J., & Martin, J. F. (2005). Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning. Development, 132, 5601–5611.

    Article  PubMed  CAS  Google Scholar 

  25. Rivera-Feliciano, J., & Tabin, C. J. (2006). Bmp2 instructs cardiac progenitors to form the heart-valve-inducing field. Developmental Biology, 295, 580–588.

    Article  PubMed  CAS  Google Scholar 

  26. Brown, C. B., Boyer, A. S., Runyan, R. B., & Barnett, J. V. (1996). Antibodies to the type ii tgfbeta receptor block cell activation and migration during atrioventricular cushion transformation in the heart. Developmental Biology, 174, 248–257.

    Article  PubMed  CAS  Google Scholar 

  27. Person, A. D., Klewer, S. E., & Runyan, R. B. (2005). Cell biology of cardiac cushion development. International Review of Cytology, 243, 287–335.

    Article  PubMed  CAS  Google Scholar 

  28. Liebner, S., Cattelino, A., Gallini, R., Rudini, N., Iurlaro, M., Piccolo, S., et al. (2004). Beta-catenin is required for endothelial-mesenchymal transformation during heart cushion development in the mouse. The Journal of Cell Biology, 166, 359–367.

    Article  PubMed  CAS  Google Scholar 

  29. Timmerman, L. A., Grego-Bessa, J., Raya, A., Bertran, E., Perez-Pomares, J. M., Diez, J., et al. (2004). Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes & Development, 18, 99–115.

    Article  CAS  Google Scholar 

  30. Combs, M. D., & Yutzey, K. E. (2009). Heart valve development: regulatory networks in development and disease. Circulation Research, 105, 408–421.

    Article  PubMed  CAS  Google Scholar 

  31. Lincoln, J., & Yutzey, K. E. (2011). Molecular and developmental mechanisms of congenital heart valve disease. Birth Defects Research. Part A, Clinical and Molecular Teratology, 91, 526–534.

    Article  PubMed  CAS  Google Scholar 

  32. Paranya, G., Vineberg, S., Dvorin, E., Kaushal, S., Roth, S. J., Rabkin, E., et al. (2001). Aortic valve endothelial cells undergo transforming growth factor-beta-mediated and non-transforming growth factor-beta-mediated transdifferentiation in vitro. American Journal of Pathology, 159, 1335–1343.

    Article  PubMed  CAS  Google Scholar 

  33. Paruchuri, S., Yang, J. H., Aikawa, E., Melero-Martin, J. M., Khan, Z. A., Loukogeorgakis, S., et al. (2006). Human pulmonary valve progenitor cells exhibit endothelial/mesenchymal plasticity in response to vascular endothelial growth factor-a and transforming growth factor-beta2. Circulation Research, 99, 861–869.

    Article  PubMed  CAS  Google Scholar 

  34. Yang, J. H., Wylie-Sears, J., & Bischoff, J. (2008). Opposing actions of notch1 and vegf in post-natal cardiac valve endothelial cells. Biochemical and Biophysical Research Communications, 374, 512–516.

    Article  PubMed  CAS  Google Scholar 

  35. Chaput, M., Handschumacher, M. D., Tournoux, F., Hua, L., Guerrero, J. L., Vlahakes, G. J., et al. (2008). Mitral leaflet adaptation to ventricular remodeling: occurrence and adequacy in patients with functional mitral regurgitation. Circulation, 118, 845–852.

    Article  PubMed  Google Scholar 

  36. Dal-Bianco, J. P., Aikawa, E., Bischoff, J., Guerrero, J. L., Handschumacher, M. D., Sullivan, S., et al. (2009). Active adaptation of the tethered mitral valve: Insights into a compensatory mechanism for functional mitral regurgitation. Circulation, 120, 334–342.

    Article  PubMed  Google Scholar 

  37. Lincoln, J., Lange, A. W., & Yutzey, K. E. (2006). Hearts and bones: shared regulatory mechanisms in heart valve, cartilage, tendon, and bone development. Developmental Biology, 294, 292–302.

    Article  PubMed  CAS  Google Scholar 

  38. Pittenger, M. F., Mackay, A. M., Beck, S. C., Jaiswal, R. K., Douglas, R., Mosca, J. D., et al. (1999). Multilineage potential of adult human mesenchymal stem cells. Science, 284, 143–147.

    Article  PubMed  CAS  Google Scholar 

  39. Wylie-Sears, J., Aikawa, E., Levine, R. A., Yang, J. H., & Bischoff, J. (2011). Mitral valve endothelial cells with osteogenic differentiation potential. Arteriosclerosis, Thrombosis, and Vascular Biology, 31, 598–607.

    Article  PubMed  CAS  Google Scholar 

  40. Melero-Martin, J. M., Khan, Z. A., Picard, A., Wu, X., Paruchuri, S., & Bischoff, J. (2007). In vivo vasculogenic potential of human blood-derived endothelial progenitor cells. Blood, 109, 4761–4768.

    Article  PubMed  CAS  Google Scholar 

  41. Ingram, D. A., Mead, L. E., Tanaka, H., Meade, V., Fenoglio, A., Mortell, K., et al. (2004). Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood, 104, 2752–2760.

    Article  PubMed  CAS  Google Scholar 

  42. Kraling, B. M., & Bischoff, J. (1998). A simplified method for growth of human microvascular endothelial cells results in decreased senescence and continued responsiveness to cytokines and growth factors. In Vitro Cellular & Developmental Biology–Animal, 34, 308–315.

    Article  CAS  Google Scholar 

  43. 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, 2181–2184.

    Article  PubMed  Google Scholar 

  44. Chen, J. H., Yip, C. Y., Sone, E. D., & Simmons, C. A. (2009). Identification and characterization of aortic valve mesenchymal progenitor cells with robust osteogenic calcification potential. American Journal of Pathology, 174, 1109–1119.

    Article  PubMed  CAS  Google Scholar 

  45. Osman, L., Yacoub, M. H., Latif, N., Amrani, M., & Chester, A. H. (2006). Role of human valve interstitial cells in valve calcification and their response to atorvastatin. Circulation, 114, I547–552.

    Article  PubMed  Google Scholar 

  46. Bouchard-Martel, J., Roussel, E., Drolet, M. C., Arsenault, M., & Couet, J. (2009). Interstitial cells from left-sided heart valves display more calcification potential than from right-sided valves: an in-vitro study of porcine valves. The Journal of Heart Valve Disease, 18, 421–428.

    PubMed  Google Scholar 

  47. Aikawa, E., Nahrendorf, M., Sosnovik, D., Lok, V. M., Jaffer, F. A., Aikawa, M., et al. (2007). Multimodality molecular imaging identifies proteolytic and osteogenic activities in early aortic valve disease. Circulation, 115, 377–386.

    Article  PubMed  CAS  Google Scholar 

  48. Arciniegas, E., Sutton, A. B., Allen, T. D., & Schor, A. M. (1992). Transforming growth factor beta 1 promotes the differentiation of endothelial cells into smooth muscle-like cells in vitro. Journal of Cell Science, 103(Pt 2), 521–529.

    PubMed  CAS  Google Scholar 

  49. Frid, M. G., Kale, V. A., & Stenmark, K. R. (2002). Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: in vitro analysis. Circulation Research, 90, 1189–1196.

    Article  PubMed  CAS  Google Scholar 

  50. Ishisaki, A., Hayashi, H., Li, A. J., & Imamura, T. (2003). Human umbilical vein endothelium-derived cells retain potential to differentiate into smooth muscle-like cells. Journal of Biological Chemistry, 278, 1303–1309.

    Article  PubMed  CAS  Google Scholar 

  51. Dudley, A. C., Khan, Z. A., Shih, S. C., Kang, S. Y., Zwaans, B. M., Bischoff, J., et al. (2008). Calcification of multipotent prostate tumor endothelium. Cancer Cell, 14, 201–211.

    Article  PubMed  CAS  Google Scholar 

  52. Zeisberg, E. M., Tarnavski, O., Zeisberg, M., Dorfman, A. L., McMullen, J. R., Gustafsson, E., et al. (2007). Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nature Medicine, 13, 952–961.

    Article  PubMed  CAS  Google Scholar 

  53. Zeisberg, E. M., & Kalluri, R. (2010). Origins of cardiac fibroblasts. Circulation Research, 107, 1304–1312.

    Article  PubMed  CAS  Google Scholar 

  54. Medici, D., Shore, E. M., Lounev, V. Y., Kaplan, F. S., Kalluri, R., & Olsen, B. R. (2010). Conversion of vascular endothelial cells into multipotent stem-like cells. Nature Medicine, 16, 1400–1406.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Vascular Biology Program and Department of Surgery, Children’s Hospital Boston and Harvard Medical School, Boston, MA, USA

    Joyce Bischoff

  2. Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Elena Aikawa

Authors
  1. Joyce Bischoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elena Aikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joyce Bischoff.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bischoff, J., Aikawa, E. Progenitor Cells Confer Plasticity to Cardiac Valve Endothelium. J. of Cardiovasc. Trans. Res. 4, 710–719 (2011). https://doi.org/10.1007/s12265-011-9312-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-011-9312-0

Keywords

Search

Navigation