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      Transforming Growth Factor-β Is Activated by Plasmin and Inhibits Smooth Muscle Cell Death in Human Saphenous Vein


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          Background: The effect of activation of endogenous transforming growth factor-β (TGF-β) on smooth muscle cell apoptosis was assessed in human saphenous vein. Methods: Segments of human saphenous vein, obtained at the time of bypass graft surgery, were cultured for 14 days. During this time, smooth muscle cells accumulated in the intima as a result of proliferation and migration, partly counterbalanced by apoptotic cell death. Results: Addition of exogenous TGF-β<sub>1</sub> had no effect on smooth muscle cell proliferation or apoptosis. However, antibody neutralization of endogenous TGF-β<sub>1</sub> caused significant increases in smooth muscle cell death in the media and intima without any change in proliferation. A plasmin inhibitor (α-N-acetyl- L-lysine methyl ester), a specific urokinase-type plasminogen activator (uPA) inhibitor (amiloride) and an anti-catalytic anti-uPA antibody all caused decreases in the tissue content of active TGF-β and increases in smooth muscle cell death in the media and intima. Conclusions: These data suggest that the amount of TGF-β in human saphenous vein is sufficient, when in the active form, to protect smooth muscle cells against apoptosis. Adding exogenous TGF-β<sub>1</sub> has no beneficial effect, but decreasing the amount of active TGF-β causes smooth muscle cells to undergo apoptosis. Plasmin, generated by uPA, appears to be an important activator of endogenous latent TGF-β.

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          Most cited references 20

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          How matrix metalloproteinases regulate cell behavior.

          The matrix metalloproteinases (MMPs) constitute a multigene family of over 25 secreted and cell surface enzymes that process or degrade numerous pericellular substrates. Their targets include other proteinases, proteinase inhibitors, clotting factors, chemotactic molecules, latent growth factors, growth factor-binding proteins, cell surface receptors, cell-cell adhesion molecules, and virtually all structural extracellular matrix proteins. Thus MMPs are able to regulate many biologic processes and are closely regulated themselves. We review recent advances that help to explain how MMPs work, how they are controlled, and how they influence biologic behavior. These advances shed light on how the structure and function of the MMPs are related and on how their transcription, secretion, activation, inhibition, localization, and clearance are controlled. MMPs participate in numerous normal and abnormal processes, and there are new insights into the key substrates and mechanisms responsible for regulating some of these processes in vivo. Our knowledge in the field of MMP biology is rapidly expanding, yet we still do not fully understand how these enzymes regulate most processes of development, homeostasis, and disease.
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            MT1-MMP: a potent modifier of pericellular microenvironment.

            Cells are regulated by many different means, and there is more and more evidence emerging that changes in the microenvironment greatly affect cell function. MT1-MMP is a type I transmembrane proteinase which participates in pericellular proteolysis of extracellular matrix (ECM) macromolecules. The enzyme is cellular collagenase essential for skeletal development, cancer invasion, growth, and angiogenesis. MT1-MMP promotes cell invasion and motility by pericellular ECM degradation, shedding of CD44 and syndecan1, and by activating ERK. Thus MT1-MMP is one of the factors that influence the cellular microenvironment and thereby affect cell-signaling pathways and eventually alters cellular behavior. As a proteinase, MT1-MMP is regulated by inhibitors, but it also requires formation of a homo-oligomer complex, localization to migration front of the cells, and internalization to become a "functionally active" cell function modifier. Developing new means to inhibit "functional activity" of MT1-MMP may be a new direction to establish treatments for the diseases that MT1-MMP mediates such as cancer and rheumatoid arthritis. Copyright 2005 Wiley-Liss, Inc.
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              Inhibition of endothelial cell movement by pericytes and smooth muscle cells: activation of a latent transforming growth factor-beta 1-like molecule by plasmin during co-culture

               D. Rifkin,  Y. Sato (1989)
              When a confluent monolayer of bovine aortic endothelial (BAE) cells is wounded with a razor blade, endothelial cells (ECs) spontaneously move into the denuded area. If bovine pericytes or smooth muscle cells (SMCs) are plated into the denuded area at low density, they block the movement of the ECs. This effect is dependent upon the number of cells plated into the wound area and contact between ECs and the plated cells. Antibodies to transforming growth factor-beta 1 (TGF-beta 1) abrogate the inhibition of BAE cell movement by pericytes or SMCs. TGF- beta 1, if added to wounded BAE cell monolayers, also inhibits cell movement. When cultured separately, BAE cells, pericytes, and SMCs each produce an inactive TGF-beta 1-like molecule which is activated in BAE cell-pericyte or BAE cell-SMC co-cultures. The activation appears to be mediated by plasmin as the inhibitory effect on cell movement in co- cultures of BAE cells and pericytes is blocked by the inclusion of inhibitors of plasmin in the culture medium.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                June 2005
                03 June 2005
                : 42
                : 3
                : 247-254
                Bristol Heart Institute, University of Bristol, Bristol, UK
                85657 J Vasc Res 2005;42:247–254
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 4, References: 31, Pages: 8
                Research Paper


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