Increased clearance explains lower plasma levels of tissue-type plasminogen activator by estradiol: Evidence for potently enhanced mannose receptor expression in mice

Several clinical studies have demonstrated an inverse relationship between circulating levels of estrogen and tissue-type plasminogen activator (t-PA) . The present study was designed to test the hypothesis that estrogens lowe r plasma levels of t-PA by increasing its clearance from the bloodstream. 1 7 alpha-Ethinyl estradiol (EE) treatment resulted in a significant increase in the clearance rate of recombinant human t-PA in mice (0.46 mL/min in tr eated mice v 0.32 mL/min in controls; P < .01). The clearance of endogenous , bradykinin-released t-PA in rats was also significantly increased after E E treatment (area under the curve [AUC], 24.9 ng/mL . min in treated animal s v 31.9 ng/mL . min in controls; P <.05). Two distinct t-PA clearance syst ems exist in vivo: the low-density lipoprotein receptor-related protein (LR P) on liver parenchymal cells and the mannose receptor on mainly liver endo thelial cells. Inhibition of LRP by intravenous injection of receptor-assoc iated protein (RAP) as a recombinant fusion protein with Salmonella japonic um glutathione S-transferase (GST) significantly retarded t-PA clearance in control mice (from 0.41 to 0.25 mL/min; n = 5, P < .001) and EE-treated mi ce (from 0.66 to 0.35 mL/min; n = 5, P < .005), but did not eliminate the d ifference in clearance capacity between the 2 experimental groups, Similar results were obtained in mice in which LRP was inhibited via overexpression of the RAP gene in liver by adenoviral gene transduction. In contrast, adm inistration of mannan, a mannose receptor antagonist, resulted in identical clearances (0.22 mL/min in controls and 0.24 mL/min in EE-treated mice). N orthern blot analysis showed a 6-fold increase in mannose receptor mRNA exp ression in the nonparenchymal liver cells of EE-treated mice, whereas the p arenchymal LRP mRMA levels remained unchanged. These findings were confirme d at the protein level by ligand blotting and Western blotting analysis. Ou r results demonstrate that EE treatment results in increased plasma clearan ce rate of t-PA via induction of the mannose receptor and could explain for the inverse relationship between estrogen status and plasma t-PA concentra tions as observed In humans. (C) 1999 by The American Society of Hematology .