BBB Seminar: Katherine A. Hajjar
The annexin A2 system and angiogenesis: Lessons from the knockout mouse
Katherine A. Hajjar
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA
Annexin A2 (A2) belongs to the annexin family of calcium-regulated, phospholipid binding proteins, twelve of which have been observed in humans. Protein S100A10, also known as p11, is an A2 binding partner that confers enhanced membrane binding capacity upon A2, and is required for translocation of A2 to the cell surface. On endothelial cells, monocytes, macrophages, trophoblast cells, and some tumor cells, the heterotetrameric (A2·p11)2 complex serves as an assembly site for plasminogen and tissue plasminogen activator, and accelerates the generation of the fibrinolytic protease plasmin. In an interesting co-regulatory mechanism, intracellular A2 controls levels of p11 by masking its polyubiquitination site, while p11 governs maximal A2 transit to the cell surface. Although the AnxA2-/- mouse displays normal embryonic vasculogenesis, postnatal angiogenesis is diminished in several in vivo assays. In addition, mice with elevated plasma homocysteine, which conjugates and disables A2, also exhibit impaired neoangiogenesis, which can be corrected by infusion of recombinant A2. A2 is upregulated in hypoxia, through the direct action of hypoxia-inducible transcription factor on a hypoxia-responsive element within the A2 promoter. Impaired angiogenesis in the AnxA2-/- mouse appears to reflect attenuated microvascular fibrinolytic capacity, based upon the observation of perivascular fibrin in the post-hyperoxic AnxA2-/- retina, and the finding that neovascularization can be repaired if fibrin formation is prevented. Together, these studies provide a mechanistic link between annexin A2-based cell surface fibrinolysis and neoangiogenesis.
Host: Anni Vedeler, Department of Biomedicine