van Hinsbergh VW, Koolwijk P.. Endothelial sprouting and angiogenesis: matrix metalloproteinases in the lead. Cardiovasc Res 78: 203-212

Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.
Cardiovascular Research (Impact Factor: 5.94). 06/2008; 78(2):203-12. DOI: 10.1093/cvr/cvm102
Source: PubMed


Sprouting angiogenesis is an invasive process that involves proteolytic activities required for the degradation of the endothelial basement membrane, cell migration with removal of obstructing matrix proteins, and generation of space in the matrix to allow endothelial cells to form a proper lumen. In the last decade it has become clear that besides these matrix-degrading properties, proteases exert additional, more subtle functions that play a key role in angiogenesis. These functions are discussed with specific emphasis on membrane type-1 matrix metalloproteinase (MT1-MMP), other MMPs, and the related ADAMs (a disintegrin and metalloproteinase domain). Proteases modulate the balance between pro- and anti-angiogenic factors by activation and modification of growth factors and chemokines, ectodomain shedding with accompanied receptor activation, shedding of cytokines from membrane-bound precursors, and generation of (matrix) protein fragments that inhibit or activate angiogenesis. Furthermore, they participate in the recruitment of leukocytes and progenitor cells, which contribute to the onset and progression of angiogenesis. Proteases facilitate the mobilization of progenitor cells in the bone marrow as well as the entry of these cells and leukocytes into the angiogenic area. The interaction between pericytes and the newly formed endothelial tubes is accompanied by silencing of MMP activities. Better understanding of the various activities of proteases may be helpful in developing more specific inhibitors that could result in tailor-made modification of proteolytic activities in disease.

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    • "Through adhesive interactions with integrins expressed on the endothelial cells surface, the ECM orchestrates complex signalling cascades within the cells and affects many fundamental aspects of their biology, including proliferation, migration, cytoskeletal organization, cell shape, survival, and ultimately blood vessel stabilization. Moreover, matrix molecules or fragments that show pro- and antiangiogenic activity (Table 1) are critical in the onset of angiogenesis and angiogenic cytokines which directly bind matrix and require proteolytic processing to become active [8]. "
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    ABSTRACT: Angiogenesis is a multistep process driven by a wide range of positive and negative regulatory factors. Extracellular matrix (ECM) plays a crucial role in the regulation of this process. The degradation of ECM, occurring in response to an angiogenic stimulus, leads to degradation or partial modification of matrix molecules, release of soluble factors, and exposure of cryptic sites with pro- and/or antiangiogenic activity. ECM molecules and fragments, resulting from proteolysis, can also act directly as inflammatory stimuli, and this can explain the exacerbated angiogenesis that drives and maintains several inflammatory diseases. In this review we have summarized some of the more recent literature data concerning the molecular control of ECM in angiogenesis in both physiological and pathological conditions.
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    • "The role of the metalloproteinase MT1-MMP (membrane-type 1 matrix metalloproteinase) was addressed in different cell types in terms of its ability to regulate sprout formation [25]. Enzymes are needed not only for the degradation of the basement membrane of endothelial cells allowing invasion into the tissue, but also for cell migration and removal of obstructing matrix proteins and for creating space in the matrix to allow generation of endothelial cell tubules [28, 29]. MT1-MMP, other MMPs, and the related ADAMs (a disintegrin and metalloproteinase domain) modulate the balance between pro- and antiangiogenic factors by activation and modification of growth factors and chemokines, ectodomain shedding with accompanied receptor activation, shedding of cytokines from membrane-bound precursors, and generation of (matrix) protein fragments that inhibit or activate angiogenesis [29]. "
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    • "It has been shown that MMPs are also involved in the recruitment and mobilization of progenitor cells from the bone marrow, and favor their incorporation at sites of injury during vascular repair. More specifically, MMP-9 is responsible for the proteolytic cleavage necessary for soluble Kit-ligand (sKitL) release from the bone marrow, which is required for the recruitment of hematopoietic stem cells [14-16]. "
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    ABSTRACT: The role of endothelial progenitor cells in vascular repair is related to their incorporation at sites of vascular lesions, differentiation into endothelial cells, and release of various angiogenic factors specifically by a subset of early outgrowth endothelial progenitor cells (EOCs). It has been shown that patients suffering from cardiovascular disease exhibit increased levels of circulating and soluble CD40 ligand (sCD40L), which may influence the function of EOCs. We have previously shown that the inflammatory receptor CD40 is expressed on EOCs and its ligation with sCD40L impairs the anti-platelet function of EOCs. In the present study, we aimed at investigating the effect of sCD40L on the function of EOCs in endothelial repair. Human peripheral blood mononuclear cell-derived EOCs express CD40 and its adaptor proteins, the tumor necrosis factor receptor-associated factors; TRAF1, TRAF2 and TRAF3. Stimulation of EOCs with sCD40L increased the expression of TRAF1, binding of TRAF2 to CD40 and phosphorylation of p38 mitogen activated protein kinase (MAPK). In an in vitro wound healing assay, stimulation of EOCs with sCD40L increased the release of matrix metalloproteinase 9 (MMP-9) in a concentration-dependent manner and significantly enhanced the angiogenic potential of cultured human umbilical vein endothelial cells (HUVECs). Inhibition of p38 MAPK reversed sCD40L-induced MMP-9 release by EOCs, whereas inhibition of MMP-9 reversed their pro-angiogenic effect on HUVECs. This study reveals the existence of a CD40L/CD40/TRAF axis in EOCs and shows that sCD40L increases the pro-angiogenic function of EOCs on cultured HUVECs by inducing a significant increase in MMP-9 release via, at least, the p38 MAPK signaling pathway.
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