Investigating Metalloproteinases MMP-2 and MMP-9 Mechanosensitivity to Feedback Loops Involved in the Regulation of In V
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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 Trocme´ • Marie-Paule Montmasson • Eric Fanchon Bertrand Toussaint • Philippe Tracqui
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Received: 14 November 2011 / Accepted: 11 January 2012 / Published online: 24 January 2012 Springer Science+Business Media B.V. 2012
Abstract 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 pseudocapillaries. 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
M.-U. Dao Thi M.-P. Montmasson P. Tracqui Faculte´ de Me´decine de Grenoble, DyCTiM team, UJF-Grenoble 1, CNRS, Laboratoire TIMC-IMAG UMR 5525, 38041 Grenoble, France M.-U. Dao Thi B. Toussaint Faculte´ de Me´decine de Grenoble, TheREx team, UJF-Grenoble 1, CNRS, Laboratoire TIMC-IMAG UMR 5525, 38041 Grenoble, France C. Trocme´ B. Toussaint BEP/DBTP, CHU Albert Michallon, BP 217, 38043 Grenoble Cedex 9, France E. Fanchon Faculte´ de Me´decine de Grenoble, BCM team, UJF-Grenoble 1, CNRS, Laboratoire TIMC-IMAG UMR 5525, 38041 Grenoble, France P. Tracqui (&) Institut de l’Inge´nierie et de l’Information de Sante´, CNRS, Laboratoire TIMC-IMAG, DyCTiM team, Pavillon Taillefer, 38706 La Tronche Cedex, France e-mail: [email protected]
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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 proMMP2 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 fir
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