VEGF increases the fibrinolytic activity of endothelial cells within fibrin matrices: involvement of VEGFR-2, tissue type plasminogen activator and matrix metalloproteinases.
Proteolysis of fibrin matrices by endothelial cells plays essential roles in the migratory and morphogenic differentiation processes underlying angiogenesis. Using an in vitro fibrinolysis model consisting of human umbilical vein endothelial cells (HUVECs) embedded in a three dimensional fibrin matrix, we show that VEGF, an angiogenic cytokine that plays a crucial role in the onset of angiogenesis, is a potent activator of HUVEC-mediated fibrinolysis. This VEGF-dependent fibrin degradation was completely abrogated by inhibitors of either the plasminogen activator/plasmin or matrix metalloproteinases (MMP) proteolytic systems, suggesting the involvement of both classes of proteases in fibrin degradation. Accordingly, VEGF-induced fibrinolysis correlated with an increase in the expression of tPA and of some MMPs, such as MT2-MMP and was completely blocked by a neutralizing antibody against tPA. Overall, these results indicate that efficient proteolysis of three dimensional fibrin matrices during VEGF-mediated angiogenesis involves a complex interplay between the MMP and plasmin-mediated proteolytic systems.
Ratel
David
D
Laboratoire de Médecine Moléculaire Ste-Justine-UQAM, Centre de Cancérologie Charles-Bruneau, Hôpital Ste-Justine, 3175 Chemin Côte-Ste-Catherine, Montréal, Qc, Canada H3T 1C5.
Mihoubi
Samira
S
Beaulieu
Edith
E
Durocher
Yves
Y
Rivard
Georges-Etienne
GE
Gingras
Denis
D
Béliveau
Richard
R
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis
D043925:Angiogenesis Inducing Agents; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D005337:Fibrin; D040301:Vascular Endothelial Growth Factor Receptor-2; D010959:Tissue Plasminogen Activator; D020782:Matrix Metalloproteinases