Date of Award

January 2011

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Vikki M. Abrahams

Subject Area(s)

Obstetrics and gynecology, Immunology

Abstract

EFFECTS OF ANTIPHOSPHOLIPID ANTIBODIES ON TROPHOBLAST-MEDIATED ANGIOGENESIS AND VASCULAR REMODELING

Tamara Y. Carroll, Melissa Mulla and Vikki M. Abrahams. Section of Reproductive Immunology, Department of Obstetrics and Gynecology, Yale University, School of Medicine, New Haven, CT.

Women with antiphospholipid antibody syndrome (APS) are at increased risk for miscarriage and preeclampsia, which are associated with diminished trophoblast invasion and limited spiral artery transformation. Antiphospholipid antibodies (aPL) specifically target the placenta by binding trophoblast beta2glycoprotein I (&beta2GPI). Thus, we determined whether aPLs alter trophoblast angiogenic factor production, endothelial tube formation, and trophoblast-endothelial cell interactions, and evaluated the effect of low molecular weight heparin (LMWH) on these responses. Human first trimester trophoblast produced significantly more VEGF, PlGF and sEng following exposure to aPL. This occurred independently of TLR4 and in both MyD88-dependent and independent manners. LMWH was unable to reverse the effects of the aPL on trophoblast VEGF and sEng production, and enhanced PlGF secretion. Strikingly, sFlt-1 secretion in the untreated and aPL-treated cells was increased in the presence of LMWH. However, aPL did not alter endothelial tube formation or trophoblast-endothelial cell interactions, nor did LMWH have an impact. In conclusion, this study demonstrates that aPL modulate the normal production of trophoblast angiogenic factors, that LMWH cannot reverse this effect, and LMWH may even enhance it. However, this altered angiogenic factor profile may not directly impact trophoblast-endothelial interactions/remodeling, suggesting that other mechanisms may be involved.

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This is an Open Access Thesis.

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