Thrombin in Pregnancy and Preeclampsia: Expression, Localization and Vasoactivity in Brain and Microvessels from Rats

Thrombin is a coagulation factor increased in pregnancy and further increased in preeclampsia (PE), a hypertensive disorder. Thrombin is also expressed in brain and may have a nonhemostatic role. We characterized thrombin expression and vasoactivity in brain cerebral parenchymal arterioles (PAs) in rat models of pregnancy and PE. PAs were isolated and pressurized from nonpregnant (NP), late-pregnant (LP) rats and rats with experimental preeclampsia (ePE). Reactivity to thrombin (1-50 U/mL) was measured in the absence and presence of inhibition of cyclooxygenase (COX) and nitric oxide synthase (NOS). Plasma levels of prothrombin, thrombin-antithrombin (TAT), tissue plasminogen activator, and plasminogen activator inhibitor-1 (PAI-1) and cerebrospinal fluid (CSF) levels of TAT were compared via ELISA. Expression of protease-activated receptor (PAR) types 1 and 2 in PAs were measured by Western blot and immunohistochemistry. Neuronal thrombin expression was quantified in brains from all groups by immunohistochemistry. Prothrombin and TAT were elevated in ePE plasma compared to NP and LP. TAT was detected in CSF from all groups and significantly elevated in LP (NP: 0.137±0.014 ng/mL, LP: 0.241±0.015 ng/mL, ePE: 0.192±0.028 ng/mL; p