Published online before print February 9, 2006, doi: 10.1161/01.ATV.0000209518.58252.17
© 2006 American Heart Association, Inc.
Brief Reviews |
Pericellular Proteases in Angiogenesis and Vasculogenesis
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.
Correspondence to Victor W.M. van Hinsbergh, PhD, Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. E-mail v.vanhinsbergh{at}vumc.nl
Series Editor: Stephanie Dimmeler
ATVB In Focus Novel Mediators and Mechanisms in Angiogenesis and Vasculogenesis
Previous Brief Reviews in this Series:
•Ferguson JE III, Kelley RW, Patterson C. Mechanisms of endothelial differentiation in embryonic vasculogenesis. 2005;26:2246–2254.
•Werner N, Nickenig G. Influence of cardiovascular risk factors on endothelial progenitor cells: limitations for therapy? 2006;26:257–266.
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 
vß3-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.
Pericellular proteases are involved in angiogenesis and vasculogenesis. They contribute to the degradation of the endothelial basal membrane, cell migration and invasion, and activation and liberation of angiogenic growth factors. They alter the properties of growth factors and cytokines by truncation, and generate protein fragments that have anti-angiogenic properties.
Key Words: endothelium • neovascularization • matrix metalloproteinases • MT-MMPs • cathepsins
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