PMID- 30352791 OWN - NLM STAT- MEDLINE DCOM- 20190916 LR - 20190916 IS - 1470-8736 (Electronic) IS - 0143-5221 (Linking) VI - 132 IP - 21 DP - 2018 Nov 15 TI - Alterations in vascular function by syncytiotrophoblast extracellular vesicles via lectin-like oxidized low-density lipoprotein receptor-1 in mouse uterine arteries. PG - 2369-2381 LID - 10.1042/CS20180639 [doi] AB - 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. CI - (c) 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society. FAU - Spaans, Floor AU - Spaans F AD - Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada. AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, Canada. FAU - Quon, Anita AU - Quon A AD - Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada. AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, Canada. FAU - Rowe, Stewart R AU - Rowe SR AD - Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada. AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, Canada. FAU - Morton, Jude S AU - Morton JS AD - Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada. AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, Canada. FAU - Kirschenman, Raven AU - Kirschenman R AD - Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada. AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, Canada. FAU - Sawamura, Tatsuya AU - Sawamura T AD - Department of Physiology, Shinshu University, Matsumoto, Japan. FAU - Tannetta, Dionne S AU - Tannetta DS AD - Department of Food and Nutritional Sciences, University of Reading, Reading, U.K. FAU - Sargent, Ian L AU - Sargent IL AD - Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, U.K. FAU - Davidge, Sandra T AU - Davidge ST AD - Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada sandra.davidge@ualberta.ca. AD - Department of Physiology University of Alberta, Edmonton, Canada. AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, Canada. LA - eng GR - MOP142320/CIHR/Canada GR - FS154313/CIHR/Canada GR - MR/J003360/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181113 PL - England TA - Clin Sci (Lond) JT - Clinical science (London, England : 1979) JID - 7905731 RN - 0 (Olr1 protein, mouse) RN - 0 (Receptors, Angiotensin) RN - 0 (Scavenger Receptors, Class E) RN - 0 (Vasoconstrictor Agents) RN - 0 (Vasodilator Agents) RN - 11062-77-4 (Superoxides) RN - 14691-52-2 (Peroxynitrous Acid) SB - IM MH - Adult MH - Animals MH - Endothelial Cells/drug effects/*metabolism MH - Extracellular Vesicles/*metabolism MH - Female MH - Human Umbilical Vein Endothelial Cells/metabolism MH - Humans MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Oxidative Stress MH - *Paracrine Communication MH - Peroxynitrous Acid/metabolism MH - Pregnancy MH - Receptors, Angiotensin/metabolism MH - Scavenger Receptors, Class E/deficiency/genetics/*metabolism MH - Signal Transduction MH - Superoxides/metabolism MH - Trophoblasts/*metabolism MH - Uterine Artery/cytology/drug effects/*metabolism MH - *Vasoconstriction/drug effects MH - Vasoconstrictor Agents/pharmacology MH - *Vasodilation/drug effects MH - Vasodilator Agents/pharmacology OTO - NOTNLM OT - LOX-1 OT - Syncytiotrophoblast extracellular vesicles OT - pregnancy OT - transgenic mice OT - vascular function EDAT- 2018/10/26 06:00 MHDA- 2019/09/17 06:00 CRDT- 2018/10/25 06:00 PHST- 2018/07/20 00:00 [received] PHST- 2018/10/01 00:00 [revised] PHST- 2018/10/22 00:00 [accepted] PHST- 2018/10/26 06:00 [pubmed] PHST- 2019/09/17 06:00 [medline] PHST- 2018/10/25 06:00 [entrez] AID - CS20180639 [pii] AID - 10.1042/CS20180639 [doi] PST - epublish SO - Clin Sci (Lond). 2018 Nov 13;132(21):2369-2381. doi: 10.1042/CS20180639. Print 2018 Nov 15.