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: Tamara Y Carroll, Melissa J Mulla, Christina S Han, Jan J Brosens, Larry W Chamley, Ian Giles, Charis Pericleous, Anisur Rahman, Anna K Sfakianaki, Michael J Paidas, Vikki M Abrahams
• Journal: American journal of reproductive immunology (New York, N.Y. : 1989) (Am J Reprod Immunol) Vol. 66 Issue 4 Pg. 286-96 (Oct 2011) ISSN: 1600-0897 [Electronic] Denmark
• PMID: 21545366 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 John Wiley & Sons A/S.

Chemical References

• Angiogenesis Inducing Agents
• Antibodies, Antiphospholipid
• Heparin, Low-Molecular-Weight
• MYD88 protein, human
• Myeloid Differentiation Factor 88
• PGF protein, human
• Pregnancy Proteins
• Vascular Endothelial Growth Factor A
• beta 2-Glycoprotein I
• Placenta Growth Factor
• FLT1 protein, human
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Adult
• Angiogenesis Inducing Agents (immunology, metabolism)
• Antibodies, Antiphospholipid (adverse effects, immunology, pharmacology)
• Antiphospholipid Syndrome (immunology, metabolism)
• Enzyme-Linked Immunosorbent Assay
• Female
• Heparin, Low-Molecular-Weight (pharmacology)
• Humans
• In Vitro Techniques
• Myeloid Differentiation Factor 88 (analysis, immunology)
• Neovascularization, Pathologic (immunology, metabolism)
• Placenta Growth Factor
• Pre-Eclampsia (immunology, metabolism, physiopathology)
• Pregnancy
• Pregnancy Proteins (biosynthesis, immunology)
• Pregnancy Trimester, First (drug effects, immunology)
• Trophoblasts (drug effects, immunology, metabolism)
• Vascular Endothelial Growth Factor A (biosynthesis, immunology)
• Vascular Endothelial Growth Factor Receptor-1 (biosynthesis, immunology, metabolism)
• beta 2-Glycoprotein I (antagonists & inhibitors, immunology, metabolism)