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Annexin II regulates fibrin homeostasis and neoangiogenesis in vivo.

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.

Pubmed ID: 14702107 RIS Download

Mesh terms: Animals | Annexin A2 | Aorta | Cell Movement | Cells, Cultured | Collagen | Endothelium, Vascular | Fibrin | Homeostasis | Kinetics | Matrix Metalloproteinases | Mice | Mice, Knockout | Muscle, Smooth, Vascular | Neovascularization, Pathologic | Organ Specificity | Vascular Endothelial Growth Factor A

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Associated grants

  • Agency: NHLBI NIH HHS, Id: P01 HL046403
  • Agency: NHLBI NIH HHS, Id: HL46403
  • Agency: NHLBI NIH HHS, Id: HL67839
  • Agency: NHLBI NIH HHS, Id: HL07423
  • Agency: NHLBI NIH HHS, Id: P01 HL067839
  • Agency: NHLBI NIH HHS, Id: HL42493
  • Agency: NHLBI NIH HHS, Id: R01 HL042493
  • Agency: NHLBI NIH HHS, Id: T32 HL007423

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