Aspirin enhances trophoblast invasion and represses soluble ... : Journal of Hypertension (original) (raw)

ORIGINAL PAPERS: Pregnancy

Aspirin enhances trophoblast invasion and represses soluble fms-like tyrosine kinase 1 production

a putative mechanism for preventing preeclampsia

Su, Mei-Tsza; Wang, Chia-Yihb,c; Tsai, Pei-Yina; Chen, Ting-Yub,c; Tsai, Hui-Linga; Kuo, Pao-Lina

aDepartment of Obstetrics and Gynecology, National Cheng Kung University Hospital

bDepartment of Cell Biology and Anatomy

cInstitute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Correspondence to Mei-Tsz Su, MD, PhD, Division of Genetics, Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 704, Taiwan. Fax: +886 6 276 6185; e-mail: [email protected]

Abbreviations: COX, cyclooxygenase; ECM, extracellular matrix; MAPK, mitogen-activated protein kinase; MMP, metalloproteinase; sFlt-1, soluble fms-like tyrosine kinase 1; VEGF, vascular endothelial growth factor

Received 16 October, 2018

Revised 19 April, 2019

Accepted 8 June, 2019

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Abstract

Objective:

Recent studies suggested that prophylactic aspirin prior to 16 weeks of gestation in high-risk patients may reduce the risk of developing preeclampsia; however, the exact mechanism of aspirin's effect on the pathophysiology of preeclampsia is not clear. This study was designed to investigate the effect of aspirin on trophoblast cell function and its effect on soluble fms-like tyrosine kinase 1 (sFlt-1) production to elucidate the preventive mechanisms for preeclampsia.

Methods and results:

We used two human trophoblastic cell lines (HTR-8/SVneo and JAR) and freshly isolated cytotrophoblasts from normal and preeclamptic placenta at term to determine the effect of aspirin on trophoblast cell function. Trophoblasts were pretreated with aspirin, and then cell functions and sFlt-1 expression were assessed. Our results showed that aspirin promoted trophoblast invasion not only in HTR-8/SVneo and JAR cells, but also in isolated cytotrophoblasts. sFlt-1 production was repressed by aspirin in a dose-dependent manner. By adding Flt-1 recombinant protein, the trophoblast invasion ability was inhibited in HTR-8/SVneo cells, which was reversed by Flt-1 small interfering ribonucleic acid knockdown. In addition, metalloproteinase 2/9 expression and activity were activated by aspirin but inhibited by sFlt-1. Aspirin also downregulated Akt phosphorylation, and trophoblast invasiveness was facilitated under Akt inhibitor treatment.

Conclusion:

Aspirin enhances cell invasiveness and inhibits sFlt-1 production in trophoblasts. Moreover, sFlt-1 itself also inhibits trophoblast invasion. Our novel findings suggest that the preeclampsia prevention effect of aspirin may be exerted through these two mechanisms.