Annexin II regulates fibrin homeostasis and neoangiogenesis in vivo

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

Agents that bind annexin A2 suppress ocular neovascularization

“…Annexin A2 is a member of the annexin family of calcium‐regulated phospholipid‐binding proteins that has been implicated in the pathogenesis of ischemia‐induced retinal NV (Ling et al, 2004). It is present in the cytosol of endothelial cells primarily as a monomer.…”

Annexin A2 Regulates Autophagy in Pseudomonas aeruginosa Infection through the Akt1–mTOR–ULK1/2 Signaling Pathway

“…Mice C57BL/6J female mice (6-8 wk) were obtained from the Jackson Laboratory (21), and anxa2 2/2 mice that are constructed based on C57BL/6J mice were kindly provided by Dr. K. Hajjar (Cornell University) (22). Exons 3 and 4 of anxa2 were disrupted with a cassette containing neomycin phosphotransferase driven by the phosphoglucokinase promoter to generate anxa2 2/2 mice (22). Animals were kept in a specific pathogenfree facility at the University of North Dakota (23).…”

Deficiency of annexins A5 and A6 induces complex changes in the transcriptome of growth plate cartilage but does not inhibit the induction of mineralization

“…Despite these findings, there are no conclusive data to support the role of AnxA5 and AnxA6 during in vivo mineralization. In fact, analysis of mice single‐deficient in AnxA5 or AnxA6 surprisingly displayed no obvious changes in skeletal development,13–15 but growth plate development was not analyzed in detail. Structural and functional similarities between the annexins point to redundant functions of these proteins within the growth plate 7, 15…”