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Published on: June 29, 2015
Homocysteine-mediated thrombosis and angiostasis in vascular pathobiology
1Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115-2394, USA. jloscalzo@partners.org
Insights
Homocysteine impairs blood clot breakdown and blood vessel growth by altering endothelial cell function. This study reveals a novel in vivo mechanism linking homocysteine to vascular disease development.
Area of Science:
- Cardiovascular Biology
- Thrombosis and Hemostasis
- Endothelial Cell Biology
Background:
- Homocysteine is linked to atherothrombosis, but in vivo mechanisms remain unclear.
- Previous work showed homocysteine modifies annexin A2, impairing plasminogen activation on endothelial cells.
- Annexin A2 is a key coreceptor for plasminogen and tissue plasminogen activator.
Purpose of the Study:
- To elucidate in vivo mechanisms of homocysteine-induced vascular disease.
- To investigate the role of annexin A2 in homocysteine's effects on fibrinolysis and angiogenesis.
- To explore the link between endothelial cell phenotype changes and vascular disease.
Main Methods:
- Utilized a dietary-induced hyperhomocysteinemic mouse model.
- Employed an annexin A2-deficient mouse model.
- Assessed fibrinolysis, perivascular fibrin, and angiogenesis in vivo.
Main Results:
- Hyperhomocysteinemic, annexin A2-deficient mice exhibited impaired fibrinolysis.
- Perivascular fibrin persistence was increased in these mice.
- Angiogenesis was attenuated, indicating angiostasis.
Conclusions:
- Homocysteine impairs in vivo fibrinolysis and angiogenesis via annexin A2 modification.
- Endothelial cell phenotype changes driven by homocysteine may link thrombosis to angiostasis.
- This provides a novel in vivo mechanism for homocysteine-dependent vascular disease.
Abstract:
The mechanisms by which homocysteine contributes to atherothrombosis are complex and their in vivo relevance uncertain. In this issue of the JCI, Jacovina and colleagues report a unique in vivo mechanism by which homocysteine may contribute to vascular disease (see the related article beginning on page 3384). This group had previously reported that homocysteine impairs endothelial cell surface plasminogen activation by posttranslationally modifying annexin A2, the coreceptor for plasminogen and tissue plasminogen activator. They now show that an annexin A2-deficient mouse rendered hyperhomocysteinemic by dietary means has impaired fibrinolysis, perivascular fibrin persistence, and attenuated angiogenesis (angiostasis). Potential mechanisms by which homocysteine-dependent changes in endothelial phenotype link thrombosis to angiostasis are reviewed and their relationship to homocysteine-dependent vascular disease considered.
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