BACKGROUND: Severe preeclampsia is characterized by hypertension, renal injury and placental dysfunction. Prothrombotic disorders are discovered in 10-20% of women with preeclampsia, providing the rationale for prescribing low-molecular-weight heparin (LMWH) in future pregnancies. Heparin has diverse molecular actions and appears to reduce the recurrence risk of preeclampsia in women without prothrombotic disorders. The placenta-derived anti-angiogenic splice-variant protein soluble vascular endothelial growth factor (VEGF) receptor-1 (sFLT1) is strongly implicated in the pathogenesis of the underlying endothelial dysfunction. As the placental syncytiotrophoblast is the principal source of sFLT1, we tested the hypothesis that heparin suppresses placental sFLT1 secretion. METHODS AND RESULTS: First trimester placental villi exposed to LMWH (0.25-25 IU mL(-1)) in an in vitro explant model significantly increased the expression and release of sFLT1 by the syncytiotrophoblast into culture media, reducing phosphorylation of FLT1 and KDR receptors in cultured human umbilical vein endothelial cells. This response was significantly diminished in placental villi from healthy term pregnancies. Placental villi from severely preeclamptic pregnancies had a higher baseline sFLT1 release, compared with first trimester placental villi and did not respond to LMWH treatment. LMWH promoted villous cytotrophoblast proliferation (BrdU incorporation) and impaired syncytial fusion-differentiation, causing syncytiotrophoblast apoptosis (by caspase 3&7 activity and TUNEL staining) and necrosis (ADP/ATP ratio). CONCLUSION: LMWH promotes sFLT1 synthesis and release from first trimester placental villi in a manner similar to that of severely preeclamptic placental villi, which antagonizes VEGF signaling in endothelial cells. These effects in part are mediated by an interaction between heparin and the cytotrophoblasts that regenerates the overlying syncytiotrophoblast responsible for sFLT1 secretion into the maternal blood.
BACKGROUND: Severe preeclampsia is characterized by hypertension, renal injury and placental dysfunction. Prothrombotic disorders are discovered in 10-20% of women with preeclampsia, providing the rationale for prescribing low-molecular-weight heparin (LMWH) in future pregnancies. Heparin has diverse molecular actions and appears to reduce the recurrence risk of preeclampsia in women without prothrombotic disorders. The placenta-derived anti-angiogenic splice-variant protein soluble vascular endothelial growth factor (VEGF) receptor-1 (sFLT1) is strongly implicated in the pathogenesis of the underlying endothelial dysfunction. As the placental syncytiotrophoblast is the principal source of sFLT1, we tested the hypothesis that heparin suppresses placental sFLT1 secretion. METHODS AND RESULTS: First trimester placental villi exposed to LMWH (0.25-25 IU mL(-1)) in an in vitro explant model significantly increased the expression and release of sFLT1 by the syncytiotrophoblast into culture media, reducing phosphorylation of FLT1 and KDR receptors in cultured human umbilical vein endothelial cells. This response was significantly diminished in placental villi from healthy term pregnancies. Placental villi from severely preeclamptic pregnancies had a higher baseline sFLT1 release, compared with first trimester placental villi and did not respond to LMWH treatment. LMWH promoted villous cytotrophoblast proliferation (BrdU incorporation) and impaired syncytial fusion-differentiation, causing syncytiotrophoblast apoptosis (by caspase 3&7 activity and TUNEL staining) and necrosis (ADP/ATP ratio). CONCLUSION:LMWH promotes sFLT1 synthesis and release from first trimester placental villi in a manner similar to that of severely preeclamptic placental villi, which antagonizes VEGF signaling in endothelial cells. These effects in part are mediated by an interaction between heparin and the cytotrophoblasts that regenerates the overlying syncytiotrophoblast responsible for sFLT1 secretion into the maternal blood.
Authors: Alan D Bolnick; Jay M Bolnick; Hamid-Reza Kohan-Ghadr; Brian A Kilburn; Omar J Pasalodos; Pankaj K Singhal; Jing Dai; Michael P Diamond; D Randall Armant; Sascha Drewlo Journal: Hum Reprod Date: 2017-06-01 Impact factor: 6.918
Authors: Jianzhong An; Magarya S Waitara; Michelle Bordas; Vidhyalakshmi Arumugam; Raymond G Hoffmann; Brian G Petrich; Uma Sinha; Paula E North; Rashmi Sood Journal: Blood Date: 2013-01-16 Impact factor: 22.113
Authors: David Hassel; Paul Cheng; Mark P White; Kathryn N Ivey; Jens Kroll; Hellmut G Augustin; Hugo A Katus; Didier Y R Stainier; Deepak Srivastava Journal: Circ Res Date: 2012-09-05 Impact factor: 17.367
Authors: Marc-Jens Kleppa; Sarah-Vanessa Erlenwein; Natallia Darashchonak; Constantin S von Kaisenberg; Frauke von Versen-Höynck Journal: PLoS One Date: 2014-06-05 Impact factor: 3.240
Authors: Huaisheng Xu; Massimo Bionaz; Deborah M Sloboda; Loreen Ehrlich; Shaofu Li; John P Newnham; Joachim W Dudenhausen; Wolfgang Henrich; Andreas Plagemann; John Rg Challis; Thorsten Braun Journal: BMC Res Notes Date: 2015-02-27
Authors: Henning Hagmann; Verena Bossung; Abdel Ali Belaidi; Alexander Fridman; S Ananth Karumanchi; Ravi Thadhani; Bernhard Schermer; Peter Mallmann; Guenter Schwarz; Thomas Benzing; Paul T Brinkkoetter Journal: PLoS One Date: 2014-01-21 Impact factor: 3.240