| Abstract: |
A central tenet of fibrinolysis is that tissue plasminogen activator-dependent(t-PA-dependent) conversion of plasminogen to active plasmin requires the presence of the cofactor/substrate fibrin. However, previous in vitro studies have suggested that the endothelial cell surface protein annexin II can stimulate t-PA-mediated plasminogen activation in the complete absence of fibrin. Here, homozygous annexin II-null mice displayed deposition of fibrin in the microvasculature and incomplete clearance of injury-induced arterial thrombi. While these animals demonstrated normal lysis of a fibrin-containing plasma clot, t-PA-dependent plasmin generation at the endothelial cell surface was markedly deficient. Directed migration of annexin II-null endothelial cells through fibrin and collagen lattices in vitro was also reduced, and an annexin II peptide mimicking sequences necessary for t-PA binding blocked endothelial cell invasion of Matrigel implants in wild-type mice. In addition, annexin II-deficient mice displayed markedly diminished neovascularization of fibroblast growth factor-stimulated cornea and of oxygen-primed neonatal retina. Capillary sprouting from annexin II-deficient aortic ring explants was markedly reduced in association with severe impairment of activation of metalloproteinase-9 and -13. These data establish annexin II as a regulator of cell surface plasmin generation and reveal that impaired endothelial cell fibrinolytic activity constitutes a barrier to effective neoangiogenesis. |
| Keywords: |
controlled study; vascular endothelial growth factor a; genetics; nonhuman; protein function; animal cell; mouse; animal; metabolism; mouse mutant; animals; mice; mice, knockout; animal tissue; cells, cultured; gelatinase b; animal experiment; animal model; cell motion; in vivo study; enzyme activation; in vitro study; peptide; angiogenesis; neovascularization, pathologic; explant; wild type; physiology; endothelium cell; molecular cloning; regulatory mechanism; amino acid sequence; kinetics; cell culture; vascular endothelium; endothelium, vascular; protein synthesis; matrix metalloproteinase; vasculotropin a; organ specificity; collagen; homozygote; cell migration; cell movement; protein induction; antibody specificity; matrigel; mouse strain; homeostasis; microvasculature; lipocortin 2; neovascularization (pathology); cell invasion; artery thrombosis; fibroblast growth factor; tissue plasminogen activator; regulator protein; cell surface protein; matrix metalloproteinases; fibrin; plasmin; muscle, smooth, vascular; cell surface; vascular smooth muscle; retina neovascularization; aorta; annexin a2; fibrinolysis; plasminogen; female; priority journal; article; collagenase 3; fibrin deposition; vascular ring
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