Acta Biotheoretica

, Volume 60, Issue 1–2, pp 21–40 | Cite as

Investigating Metalloproteinases MMP-2 and MMP-9 Mechanosensitivity to Feedback Loops Involved in the Regulation of In Vitro Angiogenesis by Endogenous Mechanical Stresses

  • Minh-Uyen Dao Thi
  • Candice Trocmé
  • Marie-Paule Montmasson
  • Eric Fanchon
  • Bertrand Toussaint
  • Philippe Tracqui
Regular Article


Angiogenesis is a complex morphogenetic process regulated by growth factors, but also by the force balance between endothelial cells (EC) traction stresses and extracellular matrix (ECM) viscoelastic resistance. Studies conducted with in vitro angiogenesis assays demonstrated that decreasing ECM stiffness triggers an angiogenic switch that promotes organization of EC into tubular cords or pseudo-capillaries. Thus, mechano-sensitivity of EC with regard to proteases secretion, and notably matrix metalloproteinases (MMPs), should likely play a pivotal role in this switching mechanism. While most studies analysing strain regulation of MMPs used cell cultured on stretched membranes, this work focuses on MMP expression during self-assembly of EC into capillary-like structures within fibrin gels, i.e. on conditions that mimics more closely the in vivo cellular mechanical microenvironment. The activity of MMP-2 and MMP-9, two MMPs that have a pivotal role in capillaries formation, has been monitored in pace with the progressive elongation of EAhy926 cells that takes place during the emergence of cellular cords. We found an increase of the zymogen proMMP-2 that correlates with the initial stages of EC cords formation. However, MMP-2 was not detected. ProMMP-9 secretion decreased, with levels of MMP-9 kept at a rather low value. In order to analyse more precisely the observed differences of EAhy926 response on fibrin and plastic substrates, we proposed a theoretical model of the mechano-regulation of proMMP-2 activation in the presence of type 2 tissue inhibitor of MMPs (TIMP-2). Using association/dissociation rates experimentally reported for this enzymatic network, the model adequately describes the synergism of proMMP-2 and TIMP-2 strain activation during pseudo-capillary morphogenesis. All together, these results provide a first step toward a systems biology approach of angiogenesis mechano-regulation by cell-generated extracellular stresses and strains.


Fibrin gel Tubulogenesis Mechanobiology Cellular traction forces Mathematical modelling Self-organization 



Minh-Uyen Dao Thi was supported by a Pre-Doc scholarship from the University Joseph Fourier, Grenoble. The authors wish to thank Dr. Yves Usson for valuable assistance in endothelial cell cords imaging by digital holographic microscopy, and Sylvie Papacatzis for technical assistance. This work was supported by a grant from the Institut Rhône-Alpin des Systèmes Complexes (IXXI).


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Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Minh-Uyen Dao Thi
    • 1
    • 3
  • Candice Trocmé
    • 2
  • Marie-Paule Montmasson
    • 1
  • Eric Fanchon
    • 4
  • Bertrand Toussaint
    • 2
    • 3
  • Philippe Tracqui
    • 1
    • 5
  1. 1.Faculté de Médecine de GrenobleDyCTiM team, UJF-Grenoble 1, CNRS, Laboratoire TIMC-IMAG UMR 5525GrenobleFrance
  2. 2.BEP/DBTP, CHU Albert MichallonGrenoble Cedex 9France
  3. 3.Faculté de Médecine de GrenobleTheREx team, UJF-Grenoble 1, CNRS, Laboratoire TIMC-IMAG UMR 5525GrenobleFrance
  4. 4.Faculté de Médecine de GrenobleBCM team, UJF-Grenoble 1, CNRS, Laboratoire TIMC-IMAG UMR 5525GrenobleFrance
  5. 5.Institut de l’Ingénierie et de l’Information de SantéCNRS, Laboratoire TIMC-IMAG, DyCTiM team, Pavillon TailleferLa Tronche CedexFrance

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