Date of Award

January 2018

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Vikki M. Abrahams

Abstract

Women with pathologic levels of antiphospholipid antibodies (aPL) are at high risk for recurrent pregnancy loss and preeclampsia. Despite treatment with low molecular weight heparin (LMWH), either alone or with low dose aspirin (ASA), the incidence of late-term complications remains high for these patients. aPL recognizing β 2 glycoprotein I (β2GPI) are particularly harmful during pregnancy as they target the placenta causing insufficient spiral artery transformation and inflammation, giving rise to obstetric APS. There have been extensive studies into the mechanisms by which aPL affect the placental trophoblast which constitutively synthesizes and expresses β2GPI. However, aPL specific for β2GPI can also bind to maternal uterine endothelial cells, but much less is known about the impact aPL have on the maternal side of the maternal-fetal interface. This study sought to characterize the effects of anti-β2GPI aPL on human endometrial endothelial cells (HEECs); the role of toll-like receptor-4 (TLR4) in the mechanism of aPL-HEEC interactions; and the influence of LMWH and ASA on aPL-mediated HEEC responses using in vitro culture systems. aPL, but not control IgG, significantly increased HEEC secretion of pro-angiogenic vascular endothelial growth factor (VEGF) and placental growth factor (PlGF); increased anti-angiogenic soluble fms-like tyrosine kinase receptor-1 (sFlt-1); inhibited basal secretion of the chemokines monocyte chemoattractant protein-1 (MCP-1), granulocyte colony-stimulating factor (G-CSF) and growth related oncogene- α (GRO-α); and impaired angiogenesis. The aPL-triggered inhibition of HEEC MCP-1 was mediated by activation of TLR4. LMWH and ASA, alone and in combination, exacerbated the aPL-induced changes in the HEEC angiogenic factor and chemokine profile. There was no reversal of the aPL-inhibition of HEEC angiogenesis by either single or combination therapy. In conclusion, HEECs produce chemokines necessary for normal trophoblast invasion, immune cell recruitment, and spiral artery remodeling. By aPL inhibiting HEEC chemokine secretion and promoting sFlt-1 release, the uterine endothelium may contribute to impaired placentation and vascular transformation in obstetric APS. Combination LMWH and ASA may further contribute to this endothelium dysfunction in women with obstetric APS.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 06/27/2019

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