Abstract | BACKGROUND AND PURPOSE:
Hypoxia during pregnancy is associated with increased uterine vascular resistance and elevated blood pressure both in women and female sheep. A previous study demonstrated a causal role of microRNA-210 (miR-210) in gestational hypoxia-induced suppression of Ca2+ sparks/spontaneous transient outward currents (STOCs) in ovine uterine arteries, but the underlying mechanisms remain undetermined. We tested the hypothesis that miR-210 perturbs mitochondrial metabolism and increases mitochondrial reactive oxygen species (mtROS) that confer hypoxia-induced suppression of STOCs in uterine arteries. EXPERIMENTAL APPROACH: Resistance-sized uterine arteries were isolated from near-term pregnant sheep and were treated ex vivo in normoxia and hypoxia (10.5% O2 ) for 48 h. KEY RESULTS:
Hypoxia increased mtROS and suppressed mitochondrial respiration in uterine arteries, which were also produced by miR-210 mimic to normoxic arteries and blocked by antagomir miR-210-LNA in hypoxic arteries. Hypoxia or miR-210 mimic inhibited Ca2+ sparks/STOCs and increased uterine arterial myogenic tone, which were inhibited by the mitochondria-targeted antioxidant MitoQ. Hypoxia and miR-210 down-regulated iron- sulfur cluster scaffold protein ( ISCU) in uterine arteries and knockdown of ISCU via siRNAs suppressed mitochondrial respiration, increased mtROS, and inhibited STOCs. In addition, blockade of mitochondrial electron transport chain with antimycin and rotenone inhibited large-conductance Ca2+ -activated K+ channels, decreased STOCs and increased uterine arterial myogenic tone. CONCLUSION AND IMPLICATIONS: This study demonstrates a novel mechanistic role for the miR-210-ISCU-mtROS axis in inhibiting Ca2+ sparks/STOCs in the maladaptation of uterine arteries and provides new insights into the understanding of mitochondrial perturbations in the pathogenesis of pregnancy complications resulted from hypoxia.
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Authors | Xiang-Qun Hu, Rui Song, Chiranjib Dasgupta, Monica Romero, Rucha Juarez, Jenna Hanson, Arlin B Blood, Sean M Wilson, Lubo Zhang |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 179
Issue 19
Pg. 4640-4654
(10 2022)
ISSN: 1476-5381 [Electronic] England |
PMID | 35776536
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. |
Chemical References |
- MIRN210 microRNA, human
- MicroRNAs
- Reactive Oxygen Species
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Topics |
- Animals
- Female
- Humans
- Hypoxia
(metabolism)
- MicroRNAs
(metabolism)
- Pregnancy
- Reactive Oxygen Species
(metabolism)
- Sheep
- Uterine Artery
(metabolism)
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