Date of Award

2022

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Sandra E Reznik

Second Advisor

Zhe-Sheng Chen

Third Advisor

John N.D. Wurpel

Abstract

Normal function of placental extravillous trophoblasts (EVT), which are responsible for uteroplacental vascular remodeling, is critical for adequate delivery of oxygen and nutrients to the developing fetus and normal fetal programming. Proliferation and invasion of spiral arteries by EVT depends upon adequate levels of folate. Multidrug resistance-associated protein 1 (MRP1), which is an efflux transporter, is known to remove folate from these cells. We hypothesized that palmitic acid (PA) increases MRP1-mediated folate removal from EVT, thereby interfering with EVTʼs role in early placental vascular remodeling. HTR8/SVneo and Swan-71 cells, first trimester human EVTs, were grown in the absence or presence of 0.5 mM and 0.7 mM PA for 72 h. PA increased ABCC1 gene expression and MRP1 protein expression in both cell lines. The rate of folate efflux from the cells into the media increased with a decrease in migration and invasion functions of the cultured cells. Treatment with N-acetyl cysteine (NAC) rescued the PA mediated upregulation of MRP1 and restored the invasion and migration of EVTs. Finally, in an MRP1 knockout subline of Swan-71 cells, there was a significant increase in the invasion and migration functions. The novel finding in this study that PA increases MRP1-mediated folate efflux provides a missing link explaining how PA compromises the in-utero environment.

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