期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 113, 期 1, 页码 38-48出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200419684
关键词
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资金
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL042493, P01HL067839, P01HL046403] Funding Source: NIH RePORTER
- NHLBI NIH HHS [HL46403, P01 HL046403, HL67839, T32 HL007423, R01 HL042493, HL07423, P01 HL067839, HL42493] Funding Source: Medline
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 11 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 11 as a regulator of cell surface plasmin generation and reveal that impaired endothelial cell fibrinolytic activity constitutes a barrier to effective neoangiogenesis.
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