Role of Lectin-like Oxidized LDL Receptor-1 and Syncytiotrophoblast Extracellular Vesicles in the Vascular Reactivity of Mouse Uterine Arteries During Pregnancy

Floor Spaans,Tatsuya Sawamura,Anita Quon,Sandra T. Davidge,Ian L. Sargent,Dionne S. Tannetta,Jude S. Morton,Raven Kirschenman

doi:10.1038/s41598-020-63205-2

Abstract

Vascular complications in pregnancy (e.g. preeclampsia) are a major source of maternal and foetal morbidity and mortality, and may be due to excessive release of placental syncytiotrophoblast-derived extracellular vesicles (STBEVs) into the maternal circulation. Increased activity of the multi-ligand scavenger receptor Lectin-like Oxidized LDL Receptor-1 (LOX-1) is associated with vascular dysfunction, and LOX-1 has been shown to interact with angiotensin II receptor type 1 (AT1). We hypothesized that STBEVs contribute to vascular dysfunction via LOX-1 and AT1 receptors during pregnancy. Uterine arteries from late pregnant wildtype and LOX-1 overexpressing mice were incubated overnight with or without STBEVs and vascular function was assessed using wire myography. STBEV-incubation decreased angiotensin II responsiveness only in wildtype mice, which coincided with decreased AT1 contribution and expression. Thus, STBEVs reduced angiotensin II responsiveness in normal pregnancy, but not in conditions of increased LOX-1 expression, suggesting that STBEVs (via LOX-1) play a role in normal adaptations to pregnancy. Oxidized LDL (a LOX-1 ligand) increased angiotensin II-induced vasoconstriction in STBEV-incubated arteries from both mouse strains, suggesting that the LOX-1 pathway may be involved in complicated pregnancies with elevated STBEVs and oxidized LDL levels (such as preeclampsia). These data increase our understanding of vascular complications during pregnancy.

Highlights

LDL Receptor-1 (LOX-1) is a multi-ligand scavenger receptor that has been reported to contribute to vascular dysfunction in many cardiovascular diseases such as atherosclerosis, diabetes and hypertension[10,11,12]
Uterine artery endothelial nitric oxide synthase expression was not different in arteries from WT compared to LOX-1tg mice and was not affected by STBEVincubation (WT + control: 14.3 ± 1.7 a.u.; WT + syncytiotrophoblast extracellular vesicles (STBEVs): 12.2 ± 1.9 a.u.; LOX-1tg +control: 12.5 ± 2.2 a.u.; LOX-1tg+STBEVs: 12.9 ± 1.8 a.u.)
We showed that increased expression of LOX-1 during pregnancy increased uterine artery nitric oxide contribution to vasodilation and resulted in impaired endothelium-dependent relaxation in the presence of oxLDL and STBEVs

Summary

Introduction

LOX-1 is a multi-ligand scavenger receptor that has been reported to contribute to vascular dysfunction in many cardiovascular diseases such as atherosclerosis, diabetes and hypertension[10,11,12]. STBEVs have been previously suggested to have a role in complicated pregnancies, as they were shown to activate endothelial and immune cells in vitro and potentially affect ex vivo vascular function[18,19,20,21,22]. Aligned with these studies, we previously showed that STBEVs reduced endothelium-dependent vasodilation in rat uterine arteries and, notably, that this was LOX-1 mediated[6]. We hypothesized that STBEVs impair vascular function during pregnancy, in conditions of increased LOX-1 expression or activation

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Conclusion