The influence of PRCP depletion in the intravascular compartment. (Top) At physiologic levels of PRCP, the enzyme contributes to the maintenance of normal blood pressure and reduces thrombosis risk in the intravascular compartment. PRCP activates prekallikrein to plasma kallikrein that then liberates bradykinin (BK) from kininogen. PRCP also degrades angiotensin II (Ang II) to angiotensin-(1-7) [Ang(1-7)].(4-6) Both BK and Ang (1-7) act on their respective endothelial cell membrane receptors, the bradykinin B2 receptor (B2R) or Mas, to increase coupled eNOS leading to NO formation, vasodilation, and thrombosis protection. (Bottom) PRCP-depleted mice are hypertensive with faster arterial thrombosis times. Reduction in aortic PRCP is associated increased tissue and cell ROS (O₂^.−) and uncoupled eNOS. These findings are associated with reduced vascular KLF2, KLF4, eNOS, and thrombomodulin (TM).