Fig. 2.

Novel mechanisms of thrombosis reduction in bdkrb2^−/− mice and klkb1^−/− mice. In bdkrb2^−/− mice (top portion) BDKRB2 depletion leads to complete absent bradykinin/BDKRB2 signaling, whereas in klkb1^−/− mice (bottom portion) prekallikrein depletion causes attenuated bradykinin formation and reduced BDKRB2 expression. Both mice have defective bradykinin/BDKRB2 signaling resulting in compensatory overexpressed Mas receptor. In bdkrb2^−/− mice, AT2R receptor is also overexpressed along with elevated plasma Ang II and Ang-(1−7) levels due to heightened ACE activity. In klkb1^−/− mice, AT2R is decreased with unchanged plasma Ang-(1−7) level. Therefore, the Ang-(1−7)/Mas axis is enhanced in both mice to produce graded elevation of plasma PGI₂ depending on the extend of bradykinin/BDKRB2 deficiency. A 2∼3-folder higher level of PGI₂ due to complete absent bradykinin/BDKRB2 signaling in bdkrb2^−/− mice causes a platelet activation defect associated with prolonged bleeding, whereas a 0.5∼1-fold higher PGI₂ due to modest deficiency of the bradykinin/BDKRB2 signaling in klkb1^−/− mice leads to increased SIRT1 and KLF4 expression and reduced vascular tissue factor expression and fibrin formation without reducing platelet function and hemostasis. Both mechanisms independently contribute to thrombosis reduction. uPAR: the urokinase plasminogen activator receptor; gC1qR: gC1q receptor; CK1: cytokeratin 1; HMW-kininogen: high-molecular-weight kininogen; BDKRB2: bradykinin B2 receptor; Ang II: angiotensin II; Ang-(1−7): angiotensin-(1−7); AT2R: angiotensin II receptor type 2; PGI₂: prostacyclin; SIRT1: sirtuin 1; KFL4: Krüppel-like factor 4.