Research Article: Syncytiotrophoblast extracellular vesicles impair rat uterine vascular function via the lectin-like oxidized LDL receptor-1

Date Published: July 3, 2017

Publisher: Public Library of Science

Author(s): Floor Spaans, Cindy K. Kao, Jude S. Morton, Anita L. Quon, Tatsuya Sawamura, Dionne S. Tannetta, Ian L. Sargent, Sandra T. Davidge, Christopher Torrens.


Syncytiotrophoblast extracellular vesicles (STBEVs) are placenta derived particles that are released into the maternal circulation during pregnancy. Abnormal levels of STBEVs have been proposed to affect maternal vascular function. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a multi-ligand scavenger receptor. Increased LOX-1 expression and activation has been proposed to contribute to endothelial dysfunction. As LOX-1 has various ligands, we hypothesized that, being essentially packages of lipoproteins, STBEVs are able to activate the LOX-1 receptor thereby impairing vascular function via the production of superoxide and decreased nitric oxide bioavailability. Uterine arteries were obtained in late gestation from Sprague-Dawley rats and incubated for 24h with or without human STBEVs (derived from a normal pregnant placenta) in the absence or presence of a LOX-1 blocking antibody. Vascular function was assessed using wire myography. Endothelium-dependent maximal vasodilation to methylcholine was impaired by STBEVs (MCh Emax: 57.7±5.9% in STBEV-incubated arteries vs. 77.8±2.9% in controls, p<0.05). This was prevented by co-incubation of STBEV-incubated arteries with LOX-1 blocking antibodies (MCh Emax: 78.8±4.3%, p<0.05). Pre-incubation of the vessels with a nitric oxide synthase inhibitor (L-NAME) demonstrated that the STBEV-induced impairment in vasodilation was due to decreased nitric oxide contribution (ΔAUC 12.2±11.7 in STBEV-arteries vs. 86.5±20 in controls, p<0.05), which was abolished by LOX-1 blocking antibody (ΔAUC 98.9±17, p<0.05). In STBEV-incubated vessels, LOX-1 inhibition resulted in an increased endothelial nitric oxide synthase expression (p<0.05), to a level similar to control vessels. The oxidant scavenger, superoxide dismutase, did not improve this impairment, nor were vascular superoxide levels altered. Our data support an important role for STBEVs in impairment of vascular function via activation of LOX-1 and reduced nitric oxide mediated vasodilation. Moreover, we postulate that the LOX-1 pathway could be a potential therapeutic target in pathologies associated with vascular dysfunction during pregnancy.

Partial Text

STBEVs are heterogeneous membranous vesicles released into the maternal circulation by the multinucleated syncytiotrophoblast layer of the placenta. They are variable in size, ranging from smaller exosomes and ectosomes (50–150 nm) to larger extracellular vesicles (100 nm—1 μm) [1], and during pregnancy they are present from the second trimester onwards, reaching their highest levels at the end of gestation [2, 3]. While STBEVs are naturally released during pregnancy, increased concentrations of STBEVs have been suggested to contribute to potential pathological states such as systemic inflammation and endothelial dysfunction [4]. Specifically, STBEVs have been shown to activate peripheral blood monocytes and peripheral blood mononuclear cells [2, 5], disrupt the monolayer architecture and reduce proliferation of endothelial cells [6]. In addition, some ex vivo studies have shown that STBEVs affect vascular function [7] while others did not observe any changes [8]. Although it has been suggested that the proteins and the danger-associated molecular patterns (DAMPs) that STBEVs carry on their surface (such as heat shock proteins) could mediate their own activity [1], the specific receptor(s) by which STBEVs act and their exact mechanism(s) of downstream action are still unknown.

In the current study, we have shown that STBEVs impaired endothelium-dependent vasodilation in uterine arteries, which appeared to be LOX-1 receptor mediated. We also demonstrated that arteries exposed to STBEVs exhibited an increased LOX-1 contribution to impaired NO-mediated vasodilation. However, vascular superoxide production was unaltered by exposure to STBEVs. Inhibition of LOX-1 in STBEV-incubated vessels increased eNOS expression. These data support our hypothesis that STBEVs can play a role in vascular dysfunction through the activation of LOX-1.




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