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.
Ling
Qi
Q
Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York 10021, USA.
Jacovina
Andrew T
AT
Deora
Arunkumar
A
Febbraio
Maria
M
Simantov
Ronit
R
Silverstein
Roy L
RL
Hempstead
Barbara
B
Mark
Willie H
WH
Hajjar
Katherine A
KA
D000818:Animals; D017306:Annexin A2 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D001011:Aorta; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology*; D005337:Fibrin / Q000378:metabolism*; D006706:Homeostasis; D007700:Kinetics; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000235:genetics*; D009928:Organ Specificity; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
D017306:Annexin A2; D042461:Vascular Endothelial Growth Factor A; D005337:Fibrin; D003094:Collagen; D020782:Matrix Metalloproteinases