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Extracellular vesicles are dynamic regulators of maternal glucose homeostasis during pregnancy.

ABSTRACT: Homeostatic regulation of the maternal milieu during pregnancy is critical for maternal and fetal health. The placenta facilitates critical communication between maternal and fetal compartments, in part, through the production of extracellular vesicles (EVs). EVs enable tissue synchrony via cell-cell and long-distance communication and are at their highest circulating concentration during pregnancy. While much work has been done investigating how physiological challenges in pregnancy affect the fetus, the role of placental communication in maternal health has not been well examined. We previously identified placental O-glycosyl transferase (OGT), a glucose-sensing enzyme, as a target of maternal stress where OGT levels and activity affected the O-glycosylation of proteins critical for EV cargo loading and secretion. Here, we hypothesized that placental OGT plays an essential role in maternal homeostatic regulation during pregnancy via its regulation of maternal circulating EV concentrations. Our studies found that changes to key metabolic factors over the circadian cycle, including glucocorticoids, insulin, and glucose, were significantly associated with changes in circulating EV concentration. Targeting placental OGT in mice, we found a novel significant positive relationship between placental OGT and maternal circulating EV concentration that was associated with improving maternal glucose tolerance during pregnancy. Finally, an intravenous elevation in EVs, matching the concentration of EVs during pregnancy, shifted non-pregnant female glucose sensitivity, blunted glucose variance, and improved synchrony of glucose uptake. These data suggest an important and novel role for circulating EVs as homeostatic regulators important in maternal health during pregnancy.

SUBMITTER: Zierden HC

PROVIDER: S-EPMC10027885 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Extracellular vesicles are dynamic regulators of maternal glucose homeostasis during pregnancy.

Zierden Hannah C HC Marx-Rattner Ruth R Rock Kylie D KD Montgomery Kristen R KR Anastasiadis Pavlos P Folts Lillian L Bale Tracy L TL

Scientific reports 20230320 1

Homeostatic regulation of the maternal milieu during pregnancy is critical for maternal and fetal health. The placenta facilitates critical communication between maternal and fetal compartments, in part, through the production of extracellular vesicles (EVs). EVs enable tissue synchrony via cell-cell and long-distance communication and are at their highest circulating concentration during pregnancy. While much work has been done investigating how physiological challenges in pregnancy affect the ...[more]

PMID: 36941297

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Project description:Introduction: SARS-CoV-2 infection may cause a severe inflammatory response, inflicting severe morbidity and mortality. This risk is modestly increased in pregnant patients. Despite the hypercoagulability and immunosuppression associated with pregnancy, most pregnant women experience a mild COVID-19 infection. Maternal extracellular vesicles (EVs) may interact with endothelial and immune components to facilitate a favorable disease course. This pilot study aimed to explore the characteristics of EVs released during COVID-19 infection occurring during the third trimester of pregnancy. Methods: In this prospective study, blood samples were obtained from 16 healthy non-pregnant (NP), 18 healthy-pregnant (HP), and 22 COVID-19 positive pregnant subjects (CoV-P). Disease course and pregnancy outcomes were assessed and EVs were characterized. Of note, limited volumes of sample acquired from the subjects made it necessary to use smaller and different subsets of samples for each analysis. Results: The majority (91%) of the COVID-19-pregnant subjects (18 mild and 2 moderate disease) experienced good pregnancy-related outcomes. EV concentrations were higher in healthy-pregnant subjects compared to non-pregnant subjects (p = 0.0041) and lower in COVID-19-pregnant subjects compared to healthy-pregnant subjects (p = 0.0150). CD63 exosome marker expression was higher in EVs of healthy-pregnant subjects and COVID-19-pregnant subjects compared to EVs of non-pregnant subjects (p = 0.0149, p = 0.0028, respectively). Similar levels of SARS-CoV-2 entry proteins (ACE-2 and TMPRSS2) were found in all three groups. Cytokine content increased in healthy-pregnant subject-EVs compared to non-pregnant EVs, while IL-2 and IL-6 levels were decreased in COVID-19-pregnant subject-EVs compared to healthy-pregnant subject-EVs (p = 0.043, p = 0.0390, respectively). CD8+, cytotoxic T-cell marker, was lower in non-pregnant EVs compared to healthy-pregnant subject-EVs and to COVID-19-pregnant subjects (p = 0.0108, p < 0.0001, respectively). COVID-19- pregnant subject-EVs demonstrated higher levels of platelet activation marker (CD62P) than non-pregnant (p = 0.0327) and healthy-pregnant subjects (p = 0.0365). Endothelial marker EV-CD144+ was lower in healthy-pregnant subjects versus non-pregnant subjects (p = 0.0093), but similar in COVID-19-pregnant and non-pregnant subjects. Other EVs' coagulation markers/activity, D-Dimer and fibrinogen levels were similar in healthy-pregnant subjects and COVID-19 positive pregnant subjects. Conclusion: COVID-19 positive pregnant subjects' EVs demonstrated an attenuated inflammatory response, with no additional activation of the coagulation system.

Project description:BackgroundMaternal hyperglycemia has been linked to adverse neonatal outcomes, including increased risk of neonatal hypoglycemia due to the stress of adapting to extrauterine life and the sudden decrease in maternal glucose supply. The association between maternal blood glucose control and neonatal conditions is crucial for developing strategies to improve neonatal health and prevent complications. This study aims to explore the correlation between maternal blood glucose levels during pregnancy and predelivery and neonatal outcomes, specifically hypoglycemia and jaundice.MethodsIn this prospective cohort study, we enrolled 710 pregnant women from a population-based sample. Demographic and obstetric data were collected, and maternal glycemic indicators, including hemoglobin A1c (HbA1c), were assessed alongside neonatal birth outcomes. A generalized linear model was employed to analyze the impact of maternal blood glucose on neonatal glucose and bilirubin levels, with Pearson correlation coefficients used to quantify relationships. Multiple regression analysis was conducted to identify key determinants of neonatal hypoglycemia and jaundice associated with maternal glycemic status.ResultsPregnant women with diabetes in pregnancy (DIP) exhibited higher fasting blood glucose (FBG), glycated albumin (GA), and HbA1c levels compared to those with normal glycemia (P<0.01), and their offspring had an increased risk of adverse birth outcomes, such as lower birth weight and a 1-minute Apgar score below 7 (P<0.01). A significant negative correlation was observed between maternal predelivery blood glucose levels and neonatal blood glucose levels at 0.5 hours after delivery (BGLU0.5) (P<0.01). Conversely, a positive association was found between maternal predelivery glucose levels and neonatal bilirubin levels on the second and third day after birth (TB2 and TB3) (P<0.05). Additionally, for every 1% increase in HbA1c and 1 mmol/L increase in 1-hour oral glucose tolerance test (OGTT-1H) results, there was a significant decrease in neonatal BGLU0.5 [95% confidence interval (CI): (-0.1505, -0.004214), (-0.1698, -0.02407)] and an increase in TB3 [95% CI: (0.05107, 0.1970), (0.007170, 0.1544)]. Only in cesarean section delivery, every 1 mmol/L increase in predelivery blood glucose levels corresponded to an increase in neonatal blood glucose levels at 1 hour after delivery (BGLU1) levels. As to natural delivery, bilirubin levels on the first day after birth (TB1) and TB3 exhibited significant correlation with GA in third trimester. Furthermore, we also found that cesarean section predisposes neonates to a higher risk of jaundice, while natural delivery tends to have a greater influence on fetal glucose levels.ConclusionsMaternal blood glucose levels significantly influence neonatal blood glucose and bilirubin levels, thereby heightening the risk of hypoglycemia and jaundice in newborns. These findings highlight the critical need for stringent glycemic control in pregnant women with DIP.

Project description:Compelling evidence in rats support the idea that gestational chronodisruption induces major changes in maternal circadian rhythms and fetal development and that these changes impact adult life at many physiological levels. Using a model of chronic photoperiod shifting throughout gestation (CPS), in which pregnant female rats (Sprague-Dawley strain; n = 16 per group) were exposed to lighting schedule manipulation every 3-4 days reversing the photoperiod completely or light/dark photoperiod (12/12; LD), we explored in the adult rat male offspring body weight gain, glucose homeostasis, adipose tissue content, adipose tissue response to norepinephrine (NE), and adipose tissue proteomic in the basal condition with standard diet (SD) and in response to high-fat diet (HFD). In adult CPS male (100-200 days old; n = 8 per group), we found increasing body weight, under SD and adiposity. Also, we found an increased response to intraperitoneal glucose (IGTT). After 12 weeks of HFD, white adipose tissue depots in CPS offspring were increased further, and higher IGTT and lower intraperitoneal insulin tolerance response were found, despite the lack of changes in food intake. In in vitro experiments, we observed that adipose tissue (WAT and BAT) glycerol response to NE from CPS offspring was decreased, and it was completely abolished by HFD. At the proteomic level, in CPS adipose tissue, 275 proteins displayed differential expression, compared with LD animals fed with a standard diet. Interestingly, CPS offspring and LD fed with HFD showed 20 proteins in common (2 upregulated and 18 downregulated). Based on these common proteins, the IPA analysis found that two functional pathways were significantly altered by CPS: network 1 (AKT/ERK) and network 2 (TNF/IL4; data are available via ProteomeXchange with identifier PXD026315). The present data show that gestational chronodisruption induced deleterious effects in adipose tissue recruitment and function, supporting the idea that adipose tissue function was programmed in utero by gestational chronodisruption, inducing deficient metabolic responses that persist into adulthood.

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Extracellular vesicles are dynamic regulators of maternal glucose homeostasis during pregnancy.

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Extracellular vesicles are dynamic regulators of maternal glucose homeostasis during pregnancy.

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