Print Email Facebook Twitter Increased clearance explains lower plasma levels of tissue-type plasminogen activator by estradiol: Evidence for potently enhanced mannose receptor expression in mice Title Increased clearance explains lower plasma levels of tissue-type plasminogen activator by estradiol: Evidence for potently enhanced mannose receptor expression in mice Author Lansink, M. Jong, M. Bijsterbosch, M. Bekkers, M. Toet, K. Havekes, L. Emeis, J. Kooistra, T. Gaubius instituut TNO Publication year 1999 Abstract 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 estrogen lower plasma levels of t-PA by increasing its clearance from the bloodstream. 17α-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 treated 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 EE treatment (area under the curve [AUC], 24.9 ng/mL min in treated animals v 31.9 ng/mL · min in controls; P < .05). Two distinct t-PA clearance systems exist in vivo: the low-density lipoprotein receptor-related protein (LRP) on liver parenchymal cells and the mannose receptor on mainly liver endothelial cells. Inhibition of LRP by intravenous injection of receptor-associated protein (RAP) as a recombinant fusion protein with Salmonella japonicum 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 mice (from 0.66 to 0.35 mL/min; n = 5, P < .005), but did not eliminate the difference 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, administration 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). Northern blot analysis showed a 6-fold increase in mannose receptor mRNA expression in the nonparenchymal liver cells of EE-treated mice, whereas the parenchymal LRP mRNA levels remained unchanged. These findings were confirmed at the protein level by ligand blotting and Western blotting analysis. Our results demonstrate that EE treatment results in increased plasma clearance rate of t-PA via induction of the mannose receptor and could explain for the inverse relationship between estrogen status and plasma t-PA concentrations as observed in humans. Chemicals/CAS: Estradiol Congeners; Ethinyl Estradiol, 57-63-6; Lectins, C-Type; mannose receptor; Mannose-Binding Lectins; Receptors, Cell Surface; Recombinant Proteins; Tissue Plasminogen Activator, EC 18.104.22.168 Subject BiologyAnimalsEndothelium, VascularEstradiol CongenersEthinyl EstradiolFibrinolysisHumansLectins, C-TypeLiverMannose-Binding LectinsMiceRatsReceptors, Cell SurfaceRecombinant ProteinsTissue Plasminogen Activator To reference this document use: http://resolver.tudelft.nl/uuid:749f482a-5c1a-44d5-b310-c00a0a77b760 TNO identifier 235125 ISSN 0006-4971 Source Blood, 94 (4), 1330-1336 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.