Multiple Roles of Proteases in Angiogenesis

  • Ester M. Weijers
  • Victor W. M. van HinsberghEmail author


Proteases play an important role in various aspects of angiogenesis. First, pericellular proteolysis facilitates matrix degradation as well as migration and invasion of capillary sprouts into its surrounding matrix. (Membrane-type) matrix metalloproteases [(MT-)MMPs], ADAM(TS) metalloproteases, serine proteases, their inhibitors, and occasionally cysteine proteases are important players in pericellular proteolysis. The specific location and short exposure of protease activity can be explained by a tread-milling model with internalization of protease–receptor complexes as was proposed for MT1-MMP/MMP2 and urokinase/urokinase receptor complexes. Second, proteolytic events play a role in regulating VEGF-induced sprouting, such as proteasomal degradation of hypoxia inducible factors (HIFs), Notch-mediated cell signaling, and turnover of VEGF receptors. Third, proteases can activate and modify growth factors and receptors and thus generate split products with new biological functions and contribute to cell recruitment. Proteases likely also contribute to formation of anastomoses, which is required to restore circulation. Finally, new biological functions are also acquired by generation of split products from and modifications of matrix proteins. They include angiogenesis-inhibiting matrikines, and modified fibrin forms with altered angiogenic properties, which may bear perspective for tissue engineering applications.


Matrix metalloproteinases Cysteine proteases VEGF Hypoxia HIF Notch signaling 



This work was supported by grants of The Netherlands Institute for Regenerative Medicine (NIRM, workpackage hypoxia and angiogenesis).


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Copyright information

© Springer-Verlag Wien 2013

Authors and Affiliations

  • Ester M. Weijers
    • 1
  • Victor W. M. van Hinsbergh
    • 1
    Email author
  1. 1.Laboratory for Physiology, Institute for Cardiovascular ResearchVU University Medical CenterAmsterdamThe Netherlands

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