Heparin Strongly Induces Soluble Fms-Like Tyrosine Kinase 1 (sFlt1) Release in vivo and in vitro

Background: Soluble fms-like tyrosine kinase 1 (sFlt1) is involved in preeclampsia and coro- nary artery disease, which share endothelial dysfunction in common. Since sFlt1 has a major heparin-binding site, we aimed to prove that sFlt1, which is “stored” by heparan sulphate proteoglycans on the cell...

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Main Authors: Herse, F, Searle, J, Vollert, JO, Slagman, A, Mueller, C, Müller, DN, Möckel, M, Dechend, R
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Searle, J
Vollert, JO
Slagman, A
Mueller, C
Müller, DN
Möckel, M
Dechend, R
description Background: Soluble fms-like tyrosine kinase 1 (sFlt1) is involved in preeclampsia and coro- nary artery disease, which share endothelial dysfunction in common. Since sFlt1 has a major heparin-binding site, we aimed to prove that sFlt1, which is “stored” by heparan sulphate proteoglycans on the cell surface and/or in the extracellular matrix, is released upon heparin administration due to a competitive mechanism. Methods: We measured sFlt1 in serial plasma samples taken at 4 time points, before and af- ter heparin administration from 135 patients undergoing elective coronary angiography (CA). We also tested our hypothesis in umbili- cal veins, villous explants, cell culture (HUVEC), and an animal model. Results: sFlt1 levels in patients (253.6 pg/ml at admission) increased significantly after heparin administration (13,440 pg/ml) by a factor of 53-fold (p < 0.001) and returned to baseline within 6 – 10h. Levels further increased after additional doses of heparin. Not only sFlt1, but also sFlt1/PLGF- and sFlt1/VEGF-ratios were significantly elevated (43-fold, 85-fold re- spectively, compared to admission, p < 0.0001). Patients' plasma sFlt1 were processed for Western blot that revealed a ˜100 kDa isoform. Heparin also significantly induced the release of sFlt1 into media by cultured HUVEC (1.4 fold), umbilical veins (2.4 fold) and villous ex- plants (1.7 fold) compared to vehicle treatment (p < 0.001). Heparinase I and III also significantly increased sFlt1 (p = 0.05). Immunohistochemistry confirmed the release of sFlt1 from the umbilical vein endothelial layer. Not only intravenous but also subcutaneous heparin treatment in mice, increased sFlt1 in plasma (43,186.6 pg/ml and16,095.1 pg/ml respectively, vs. 895.6 pg/ml at baseline p < 0.01). Conclusions: Heparin releases high amounts of sFlt1 by competitively displacing the sFlt1 heparin-binding site from its connection to heparan sulphate proteoglycans. Heparin ad- ministration thereby induces an acute anti- angiogenic state in the circulation
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Since sFlt1 has a major heparin-binding site, we aimed to prove that sFlt1, which is “stored” by heparan sulphate proteoglycans on the cell surface and/or in the extracellular matrix, is released upon heparin administration due to a competitive mechanism. Methods: We measured sFlt1 in serial plasma samples taken at 4 time points, before and af- ter heparin administration from 135 patients undergoing elective coronary angiography (CA). We also tested our hypothesis in umbili- cal veins, villous explants, cell culture (HUVEC), and an animal model. Results: sFlt1 levels in patients (253.6 pg/ml at admission) increased significantly after heparin administration (13,440 pg/ml) by a factor of 53-fold (p &lt; 0.001) and returned to baseline within 6 – 10h. Levels further increased after additional doses of heparin. Not only sFlt1, but also sFlt1/PLGF- and sFlt1/VEGF-ratios were significantly elevated (43-fold, 85-fold re- spectively, compared to admission, p &lt; 0.0001). Patients' plasma sFlt1 were processed for Western blot that revealed a ˜100 kDa isoform. Heparin also significantly induced the release of sFlt1 into media by cultured HUVEC (1.4 fold), umbilical veins (2.4 fold) and villous ex- plants (1.7 fold) compared to vehicle treatment (p &lt; 0.001). Heparinase I and III also significantly increased sFlt1 (p = 0.05). Immunohistochemistry confirmed the release of sFlt1 from the umbilical vein endothelial layer. Not only intravenous but also subcutaneous heparin treatment in mice, increased sFlt1 in plasma (43,186.6 pg/ml and16,095.1 pg/ml respectively, vs. 895.6 pg/ml at baseline p &lt; 0.01). Conclusions: Heparin releases high amounts of sFlt1 by competitively displacing the sFlt1 heparin-binding site from its connection to heparan sulphate proteoglycans. 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Patients' plasma sFlt1 were processed for Western blot that revealed a ˜100 kDa isoform. Heparin also significantly induced the release of sFlt1 into media by cultured HUVEC (1.4 fold), umbilical veins (2.4 fold) and villous ex- plants (1.7 fold) compared to vehicle treatment (p &lt; 0.001). Heparinase I and III also significantly increased sFlt1 (p = 0.05). Immunohistochemistry confirmed the release of sFlt1 from the umbilical vein endothelial layer. Not only intravenous but also subcutaneous heparin treatment in mice, increased sFlt1 in plasma (43,186.6 pg/ml and16,095.1 pg/ml respectively, vs. 895.6 pg/ml at baseline p &lt; 0.01). Conclusions: Heparin releases high amounts of sFlt1 by competitively displacing the sFlt1 heparin-binding site from its connection to heparan sulphate proteoglycans. 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Patients' plasma sFlt1 were processed for Western blot that revealed a ˜100 kDa isoform. Heparin also significantly induced the release of sFlt1 into media by cultured HUVEC (1.4 fold), umbilical veins (2.4 fold) and villous ex- plants (1.7 fold) compared to vehicle treatment (p &lt; 0.001). Heparinase I and III also significantly increased sFlt1 (p = 0.05). Immunohistochemistry confirmed the release of sFlt1 from the umbilical vein endothelial layer. Not only intravenous but also subcutaneous heparin treatment in mice, increased sFlt1 in plasma (43,186.6 pg/ml and16,095.1 pg/ml respectively, vs. 895.6 pg/ml at baseline p &lt; 0.01). Conclusions: Heparin releases high amounts of sFlt1 by competitively displacing the sFlt1 heparin-binding site from its connection to heparan sulphate proteoglycans. Heparin ad- ministration thereby induces an acute anti- angiogenic state in the circulation</abstract><doi>10.1055/s-0033-1347752</doi><oa>free_for_read</oa></addata></record>
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title Heparin Strongly Induces Soluble Fms-Like Tyrosine Kinase 1 (sFlt1) Release in vivo and in vitro
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