Blood Journal
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Angiotensin 1-7 and Mas decrease thrombosis in Bdkrb2−/− mice by increasing NO and prostacyclin to reduce platelet spreading and glycoprotein VI activation

  1. Chao Fang1,2,
  2. Evi Stavrou1,
  3. Alec A. Schmaier3,
  4. Nadja Grobe4,
  5. Mariana Morris4,
  6. Andrew Chen1,
  7. Marvin T. Nieman1,
  8. Gregory N. Adams1,2,
  9. Gretchen LaRusch1,
  10. Yihua Zhou1,
  11. Matthew L. Bilodeau5,
  12. Fakhri Mahdi6,
  13. Mark Warnock7, and
  14. Alvin H. Schmaier1,2
  1. 1Hematology and Oncology Division, Department of Medicine, and
  2. 2Department of Pathology, Case Western Reserve University, Cleveland, OH;
  3. 3Department of Medicine, University of Pennsylvania, Philadelphia, PA;
  4. 4Department of Pharmacology and Toxicology, Wright State University Boonshoft School of Medicine, Dayton, OH;
  5. 5Cardiology Section, Lutheran Medical Group, Fort Wayne, IN;
  6. 6Department of Pharmacology, University of Mississippi, Oxford, MS; and
  7. 7Department of Medicine, University of Michigan, Ann Arbor, MI
This article has an Erratum 123(10):1622

Key Points

  • In Bdkrb2−/− mice, compensatory Mas and AT2R overexpression elevates NO and PGI2 to prolong bleeding times and delay arterial thrombosis.

  • This NO and PGI2 elevation attenuates platelet integrin-dependent spreading and GPVI responses without altering thrombin or ADP activation.


Bradykinin B2 receptor–deleted mice (Bdkrb2−/−) have delayed carotid artery thrombosis times and prolonged tail bleeding time resulting from elevated angiotensin II (AngII) and angiotensin receptor 2 (AT2R) producing increased plasma nitric oxide (NO) and prostacyclin. Bdkrb2−/− also have elevated plasma angiotensin-(1-7) and messenger RNA and protein for its receptor Mas. Blockade of Mas with its antagonist A-779 in Bdkrb2−/− shortens thrombosis times (58 ± 4 minutes to 38 ± 4 minutes) and bleeding times (170 ± 13 seconds to 88 ± 8 seconds) and lowers plasma nitrate (22 ± 4 μM to 15 ± 5 μM), and 6-keto-PGF (259 ± 103 pg/mL to 132 ± 58 pg/mL). Bdkrb2−/− platelets express increased NO, guanosine 3′,5′-cyclic monophosphate, and cyclic adenosine monophosphate with reduced spreading on collagen, collagen peptide GFOGER, or fibrinogen. In vivo A-779 or combined L-NAME and nimesulide treatment corrects it. Bdkrb2−/− platelets have reduced collagen-related peptide–induced integrin α2bβ3 activation and P-selectin expression that are partially corrected by in vivo A-779, nimesulide, or L-NAME. Bone marrow transplantations show that the platelet phenotype and thrombosis time depends on the host rather than donor bone marrow progenitors. Transplantation of wild-type bone marrow into Bdkrb2−/− hosts produces platelets with a spreading defect and delayed thrombosis times. In Bdkrb2−/−, combined AT2R and Mas overexpression produce elevated plasma prostacyclin and NO leading to acquired platelet function defects and thrombosis delay.

  • Submitted September 25, 2012.
  • Accepted January 28, 2013.
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