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on February 9, 2006

Arteriosclerosis, Thrombosis, and Vascular Biology. 2006
Published online before print February 9, 2006, doi: 10.1161/01.ATV.0000209518.58252.17
A more recent version of this article appeared on April 1, 2006
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*Substance via MeSH

Submitted on November 8, 2005
Accepted on January 25, 2006

Pericellular Proteases in Angiogenesis and Vasculogenesis

Victor W.M. van Hinsbergh *; Marten A. Engelse ; and Paul H.A. Quax

From the Laboratory for Physiology (V.W.M.H., M.A.E.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam; TNO Quality of Life (P.H.A.Q.), Gaubius Laboratory, Dept. Biomedical Research, Leiden, The Netherlands.

* To whom correspondence should be addressed. E-mail: v.vanhinsbergh{at}vumc.nl.

Abstract--Pericellular proteases play an important role in angiogenesis and vasculogenesis. They comprise (membrane-type) matrix metalloproteinases [(MT-)MMPs], serine proteases, cysteine cathepsins, and membrane-bound aminopeptidases. Specific inhibitors regulate them. Major roles in initiating angiogenesis have been attributed to MT1-matrix metalloproteinase (MMP), MMP-2, and MMP-9. Whereas MT-MMPs are membrane-bound by nature, MMP-2 and MMP-9 can localize to the membrane by binding to {alpha}v{beta}3-integrin and CD44, respectively. Proteases switch on neovascularization by activation, liberation, and modification of angiogenic growth factors and degradation of the endothelial and interstitial matrix. They also modify the properties of angiogenic growth factors and cytokines. Neovascularization requires cell migration, which depends on the assembly of protease-protein complexes at the migrating cell front. MT1-MMP and urokinase (u-PA) form multiprotein complexes in the lamellipodia and focal adhesions of migrating cells, facilitating proteolysis and sufficient support for endothelial cell migration and survival. Excessive proteolysis causes loss of endothelial cell-matrix interaction and impairs angiogenesis. MMP-9 and cathepsin L stimulate the recruitment and action of blood- or bone-marrow-derived accessory cells that enhance angiogenesis. Proteases also generate fragments of extracellular matrix and hemostasis factors that have anti-angiogenic properties. Understanding the complexity of protease activities in angiogenesis contributes to recognizing new targets for stimulation or inhibition of neovascularization in disease.




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