Syncytiotrophoblast extracellular vesicles (STBEVs), released into the maternal circulation during pregnancy, have been shown to affect vascular function; however, the mechanism remains unknown. In rats, STBEVs were shown to reduce endothelium-mediated vasodilation via lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a multi-ligand scavenger receptor that has been associated with vascular dysfunction. Recently, LOX-1 was shown to interact with the angiotensin II type 1 receptor (AT-1). We hypothesized that, in pregnant mice, STBEVs would impair vascular function via LOX-1 and would specifically affect angiotensin II responses. Uterine arteries from pregnant control (C57BL/6) and LOX-1 knockout (LOX-1KO) mice were isolated on gestational day (GD) 18.5. Endothelium-dependent (methylcholine (MCh); ± N(G)-Nitro-L-arginine methyl ester to assess nitric oxide (NO) contribution), and -independent (sodium nitroprusside) vasodilation, and vasoconstriction (angiotensin II; ± AT-1 [candesartan] or angiotensin II type 2 receptor (AT-2) [PD123.319] receptor antagonists; high potassium salt solution) responses were assessed using wire myography. AT-1 and AT-2 expression was analyzed using fluorescence microscopy. Human umbilical vein endothelial cells (HUVECs) were stimulated with STBEVs ± LOX-1 blocking antibody, and superoxide and peroxynitrite production were analyzed. Although MCh-induced vasodilation was decreased (P=0.0012), NO contribution to vasodilation was greater in LOX-1KO mice (P=0.0055). STBEVs delayed angiotensin II tachyphylaxis in arteries from control but not LOX-1KO mice (P<0.0001), while AT-1 and AT-2 expression was unchanged. STBEVs increased peroxynitrite production in HUVECs via LOX-1 (P=0.0091). In summary, LOX-1 deletion altered endothelium-mediated vasodilation, suggesting that LOX-1 contributes to vascular adaptations in pregnancy. STBEVs increased angiotensin II responsiveness and oxidative stress levels via LOX-1, suggesting that increased LOX-1 expression/activation or STBEVs could adversely affect vascular function and contribute to vascular complications of pregnancy.
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α-Smooth muscle actin staining of perinatal nicotine exposed bone marrow mesenchymal stem cells (BMSCs) upon myogenic induction. In Clinical Science volume 132, issue 21, Sakurai et al. report that perinatal nicotine-induced BMSC myofibroblast differentiation can be prevented by augmenting the lipofibroblast phenotype; for details, see pages 2357–2368.Close Modal
Research Article|
November 13 2018
Alterations in vascular function by syncytiotrophoblast extracellular vesicles via lectin-like oxidized low-density lipoprotein receptor-1 in mouse uterine arteries
Floor Spaans;
Floor Spaans
1Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada
3Women and Children’s Health Research Institute, University of Alberta, Edmonton, Canada
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Anita Quon;
Anita Quon
1Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada
3Women and Children’s Health Research Institute, University of Alberta, Edmonton, Canada
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Stewart R. Rowe;
Stewart R. Rowe
1Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada
3Women and Children’s Health Research Institute, University of Alberta, Edmonton, Canada
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Jude S. Morton;
Jude S. Morton
1Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada
3Women and Children’s Health Research Institute, University of Alberta, Edmonton, Canada
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Raven Kirschenman;
Raven Kirschenman
1Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada
3Women and Children’s Health Research Institute, University of Alberta, Edmonton, Canada
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Tatsuya Sawamura;
Tatsuya Sawamura
4Department of Physiology, Shinshu University, Matsumoto, Japan
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Dionne S. Tannetta;
Dionne S. Tannetta
5Department of Food and Nutritional Sciences, University of Reading, Reading, U.K.
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Ian L. Sargent;
Ian L. Sargent
6Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, U.K.
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Sandra T. Davidge
1Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada
2Department of Physiology University of Alberta, Edmonton, Canada
3Women and Children’s Health Research Institute, University of Alberta, Edmonton, Canada
Correspondence: Sandra T. Davidge (sandra.davidge@ualberta.ca)
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Clin Sci (Lond) (2018) 132 (21): 2369–2381.
Article history
Received:
July 20 2018
Revision Received:
October 01 2018
Accepted:
October 22 2018
Accepted Manuscript online:
October 23 2018
Citation
Floor Spaans, Anita Quon, Stewart R. Rowe, Jude S. Morton, Raven Kirschenman, Tatsuya Sawamura, Dionne S. Tannetta, Ian L. Sargent, Sandra T. Davidge; Alterations in vascular function by syncytiotrophoblast extracellular vesicles via lectin-like oxidized low-density lipoprotein receptor-1 in mouse uterine arteries. Clin Sci (Lond) 15 November 2018; 132 (21): 2369–2381. doi: https://doi.org/10.1042/CS20180639
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