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Angiotensin 1-7 and Mas decrease thrombosis in Bdkrb2-/- mice by increasing NO and prostacyclin to reduce platelet
Chao Fang1, Evi Stavrou, Alec A Schmaier
1Hematology and Oncology Division, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
Blood
|February 7, 2013
Summary
Mice lacking the bradykinin B2 receptor show delayed blood clotting and bleeding due to increased nitric oxide and prostacyclin. Blocking the Mas receptor in these mice normalized clotting and bleeding times, indicating its role in platelet function.
Area of Science:
- Cardiovascular Biology
- Hemostasis and Thrombosis
- Platelet Physiology
Background:
- Bradykinin B2 receptor knockout (Bdkrb2(-/-)) mice exhibit prolonged thrombosis and bleeding times.
- This phenotype is linked to elevated angiotensin II (AngII) and angiotensin receptor 2 (AT2R), leading to increased nitric oxide (NO) and prostacyclin.
- Elevated plasma angiotensin-(1-7) and its receptor Mas are also observed in Bdkrb2(-/-) mice.
Purpose of the Study:
- To investigate the role of the Mas receptor and its signaling pathway in the hemostatic defects observed in Bdkrb2(-/-) mice.
- To determine the impact of Mas receptor blockade on platelet function and thrombosis in the absence of the bradykinin B2 receptor.
Main Methods:
- Pharmacological blockade of the Mas receptor using A-779 in Bdkrb2(-/-) mice.
- Measurement of carotid artery thrombosis time and tail bleeding time.
- Quantification of plasma levels of nitrate and 6-keto-PGF1α.
- Analysis of platelet function, including NO production, cyclic nucleotide levels, spreading assays, and integrin activation.
Main Results:
- Mas receptor blockade with A-779 significantly shortened thrombosis and bleeding times in Bdkrb2(-/-) mice.
- A-779 treatment reduced plasma nitrate and 6-keto-PGF1α levels.
- Bdkrb2(-/-) platelets showed impaired spreading and reduced integrin α2bβ3 activation and P-selectin expression, which were partially corrected by A-779.
- Bone marrow transplantation studies indicated that the platelet phenotype and thrombosis time are host-dependent.
Conclusions:
- Combined overexpression of AT2R and Mas in Bdkrb2(-/-) mice leads to elevated prostacyclin and NO, causing acquired platelet dysfunction and delayed thrombosis.
- The Mas receptor plays a critical role in mediating the hemostatic defects in bradykinin B2 receptor-deficient mice.
- Targeting the Mas receptor pathway offers a potential therapeutic strategy for modulating platelet function and thrombosis.
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