title: Modulation of trophoblast angiogenic factor secretion by antiphospholipid antibodies is not reversed by heparin.
abstract: PROBLEM  Women with antiphospholipid antibodies (aPL) are at risk of miscarriage and pre-eclampsia, obstetrical disorders associated with reduced trophoblast invasion and spiral artery transformation. aPL target the placenta by binding beta(2) -glycoprotein I (β(2) GPI) on the trophoblast. In this study, we determined whether aPL alter the trophoblast secretion of angiogenic factors and evaluated the effect of low molecular weight heparin (LMWH) on this response. METHOD OF STUDY  First-trimester trophoblast was treated with anti-β(2) GPI antibodies with or without LMWH. Angiogenic factor secretion was measured by enzyme-linked immunosorbent assay. RESULTS  Trophoblast cells produced more vascular endothelial growth factor (VEGF), placenta growth factor (PlGF), and soluble endoglin following exposure to anti-β(2) GPI Abs, and this occurred in both a MyD88-dependent and MyD88-independent manner. LMWH was unable to reverse the effects of the anti-β(2) GPI Abs on trophoblast VEGF secretion, but enhanced PlGF. Strikingly, LMWH upregulated soluble fms-like tyrosine kinase receptor-1 (sFlt-1) secretion independently of aPL. CONCLUSION  This study demonstrates that aPL perturb the secretion of trophoblast angiogenic factors. LMWH does not reverse this effect but exacerbates sFlt-1 secretion, a potent anti-angiogenic factor. These findings may help to explain why women with antiphospholipid syndrome, who are treated with heparin to prevent early pregnancy loss, remain at increased risk of developing late obstetrical complications, such as pre-eclampsia.
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Tamara Y
authors.initials: TY
authors.lastname: Carroll
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Mulla
authors.forename: Christina S
authors.initials: CS
authors.lastname: Han
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Brosens
authors.forename: Larry W
authors.initials: LW
authors.lastname: Chamley
authors.forename: Ian
authors.initials: I
authors.lastname: Giles
authors.forename: Charis
authors.initials: C
authors.lastname: Pericleous
authors.forename: Anisur
authors.initials: A
authors.lastname: Rahman
authors.forename: Anna K
authors.initials: AK
authors.lastname: Sfakianaki
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Paidas
authors.forename: Vikki M
authors.initials: VM
authors.lastname: Abrahams
mesh_terms: D000328:Adult; D043925:Angiogenesis Inducing Agents / Q000276:immunology* / Q000378:metabolism; D017152:Antibodies, Antiphospholipid / Q000009:adverse effects / Q000276:immunology / Q000494:pharmacology*; D016736:Antiphospholipid Syndrome / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D053594:Myeloid Differentiation Factor 88 / Q000032:analysis / Q000276:immunology; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism; D000072483:Placenta Growth Factor; D011225:Pre-Eclampsia / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000096:biosynthesis / Q000276:immunology; D011261:Pregnancy Trimester, First / Q000187:drug effects* / Q000276:immunology; D014327:Trophoblasts / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000276:immunology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D053482:beta 2-Glycoprotein I / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D017152:Antibodies, Antiphospholipid; D006495:Heparin, Low-Molecular-Weight; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D053482:beta 2-Glycoprotein I; D000072483:Placenta Growth Factor; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1