Activation of plasminogen into plasmin at the surface of endothelial microparticles: a mechanism that modulates angiogenic properties of endothelial progenitor cells in vitro.
The regulation of plasmin generation on cell surfaces is of critical importance in the control of vascular homeostasis. Cell-derived microparticles participate in the dissemination of biological activities. However, their capacity to promote plasmin generation has not been documented. In this study, we show that endothelial microparticles (EMPs) from tumor necrosis factor alpha (TNFalpha)-stimulated endothelial cells served as a surface for the generation of plasmin. The generation of plasmin involved expression of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) at the surface of EMPs and was further increased by their ability to bind exogenous uPA on uPAR. Plasminogen was activated at the surface of EMPs in a dose-dependent, saturable, and specific manner as indicated by the inhibition of plasmin formation by epsilon-amino-caproic acid (epsilon-ACA) and carboxypeptidase B. EMP-induced plasmin generation affects tube formation mediated by endothelial progenitor cells. However, low amounts of EMPs increased tube formation, whereas higher concentrations inhibited it. Prevention of these effects by inhibitors of either uPA or plasmin underscore the key role of EMP-induced plasmin generation. In conclusion, we demonstrated that EMPs act as vectors supporting efficient plasmin generation and dissemination, a new pathway in the regulation of endothelial proteolytic activities with potential involvement in inflammation, angiogenesis, and atherosclerosis.
Lacroix
Romaric
R
Unité Mixte de Recherche S 608 (UMR-S 608), Institut National de la Santé et de la Recherche Médicale (INSERM), Université de la Méditerranée, Unité de Formation et de Recherche (UFR) de Pharmacie, Marseille, France.
Sabatier
Florence
F
Mialhe
Agnès
A
Basire
Agnès
A
Pannell
Ralph
R
Borghi
Hélène
H
Robert
Stephane
S
Lamy
Edouard
E
Plawinski
Laurent
L
Camoin-Jau
Laurence
L
Gurewich
Victor
V
Angles-Cano
Eduardo
E
Dignat-George
Françoise
F
D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005341:Fibrinolysin / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D010958:Plasminogen / Q000378:metabolism*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D013234:Stem Cells / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology
C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D010958:Plasminogen; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator