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Ggps1 deficiency in the uterus results in dystocia by disrupting uterine contraction.

ABSTRACT: Dystocia is a serious problem for pregnant women, and it increases the cesarean section rate. Although uterine dysfunction has an unknown etiology, it is responsible for cesarean delivery and clinical dystocia, resulting in neonatal morbidity and mortality; thus, there is an urgent need for novel therapeutic agents. Previous studies indicated that statins, which inhibit the mevalonate (MVA) pathway of cholesterol synthesis, can reduce the incidence of preterm birth, but the safety of statins for pregnant women has not been thoroughly evaluated. Therefore, to unambiguously examine the function of the MVA pathway in pregnancy and delivery, we employed a genetic approach by using myometrial cell-specific deletion of geranylgeranyl pyrophosphate synthase (Ggps1) mice. We found that Ggps1 deficiency in myometrial cells caused impaired uterine contractions, resulting in disrupted embryonic placing and dystocia. Studies of the underlying mechanism suggested that Ggps1 is required for uterine contractions to ensure successful parturition by regulating RhoA prenylation to activate the RhoA/Rock2/p-MLC pathway. Our work indicates that perturbing the MVA pathway might result in problems during delivery for pregnant females, but modifying protein prenylation with supplementary farnesyl pyrophosphate or geranylgeranyl pyrophosphate might be a strategy to avoid side effects.

SUBMITTER: Sang YJ

PROVIDER: S-EPMC8104943 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Ggps1 deficiency in the uterus results in dystocia by disrupting uterine contraction.

Sang Yong-Juan YJ Wang Qiang Q Zheng Feng F Hua Yue Y Wang Xin-Ying XY Zhang Jing-Zi JZ Li Kang K Wang Hai-Quan HQ Zhao Yue Y Zhu Min-Sheng MS Sun Hai-Xiang HX Li Chao-Jun CJ

Journal of molecular cell biology 20210501 2

Dystocia is a serious problem for pregnant women, and it increases the cesarean section rate. Although uterine dysfunction has an unknown etiology, it is responsible for cesarean delivery and clinical dystocia, resulting in neonatal morbidity and mortality; thus, there is an urgent need for novel therapeutic agents. Previous studies indicated that statins, which inhibit the mevalonate (MVA) pathway of cholesterol synthesis, can reduce the incidence of preterm birth, but the safety of statins for ...[more]

PMID: 33340314

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Project description:IntroductionUterus bioengineering offers a potential treatment option for women with uterine factor infertility and for mitigating the risk of uterine rupture associated with women with defective uterine tissue. Decellularized uterine tissue scaffolds proved promising in further in vivo experiments in rodent and domestic species animal models. Variations in the extracellular matrix composition among different species and adaptations of the decellularization protocols make it difficult to compare the results between studies. Therefore, we assessed if our earlier developed sodium deoxycholate-based decellularization protocol for the sheep and the cow uterus could become a standardized cross-species protocol by assessing it on the non-human primate (baboon) uterus.Material and methodsThe baboon uterus was decellularized using sodium deoxycholate, and the remaining acellular scaffold was quantitatively assessed for DNA, protein, and specific extracellular matrix components. Furthermore, electron microscopy deepened morphology examination, while the chorioallantoic membrane assay examined the scaffolds' cytotoxicity, bioactivity, and angiogenic properties. The in vitro recellularization efficiency of the scaffolds using xenogeneic (rat) bone marrow-derived mesenchymal stem cells was also assessed. Finally, the immune potential of the scaffolds was evaluated by in vitro exposure to human peripheral blood mononuclear cells.ResultsWe obtained a decellularized baboon uterus with preserved extracellular matrix components by adding an 8-h sodium deoxycholate perfusion to our previously developed protocol for the sheep and cow models. This minor modification resulted in scaffolds with less than 1% of immunogenic host DNA content while preserving important uterine-specific collagen, elastin, and glycosaminoglycan structures. The chorioallantoic membrane assay and in vitro recellularization experiments confirmed that the scaffolds were bioactive and non-cytotoxic. As we have observed in other animal models, the enzymatic scaffold preconditioning with matrix metalloproteinases improved the recellularization efficiency further. Additionally, the preconditioning generated more immune-privileged scaffolds, as shown in a novel in vitro co-culture assay with human peripheral blood mononuclear cells.ConclusionsFor the first time, our data demonstrate the efficiency of our protocol for non-human primate uteri and its translational potential. This standardized protocol will facilitate cross-study comparisons and expedite clinical translation.

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Ggps1 deficiency in the uterus results in dystocia by disrupting uterine contraction.

Publications

Ggps1 deficiency in the uterus results in dystocia by disrupting uterine contraction.

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