Placental cells secrete extracellular vesicles that may play a role in regulating blood sugar during pregnancy

Placental cells secrete extracellular vesicles—tiny, balloon-like structures containing proteins, enzymes, DNA, and other molecules capable of transmitting chemical messages between cells—that appear to help regulate glucose uptake by maternal cells, according to a mouse study funded by the  National Institute of Child Health and Human Development. In a series of experiments, researchers from the University of Maryland found evidence that release of the vesicles follows placental release of the enzyme O-glycosyl transferase (OGT) after glucose levels rise. The findings may inform the development of new treatments for gestational (pregnancy-related) diabetes.

Background

Gestational diabetes refers to high blood sugar that first occurs during pregnancy. Although treatable, it is associated with a higher risk of maternal high blood pressure, large-bodied babies, cesarean delivery (C-section), and low blood sugar in newborns.

Previous studies have found that the placenta releases extracellular vesicles to communicate with maternal cells. Extracellular vesicles released during pregnancy have been associated with implantation of the embryo, activation of the maternal and fetal immune system, formation of new blood vessels, glucose uptake, and the beginning of labor. During pregnancy, the concentration of extracellular vesicles increases three or four times from non-pregnancy levels. In an earlier study, the researchers found that maternal stress reduced the levels of OGT, which senses glucose. Lowering the level of the enzyme also reduced the processing of proteins needed to produce extracellular vesicles.

For the current study, the investigators conducted a series of experiments on how stress and OGT might influence the concentration of extracellular vesicles in the blood of pregnant and non-pregnant mice.

Results

Pregnant mice injected with insulin had a much greater concentration of extracellular vesicles, compared to mice that did not receive an injection.

Extracellular vesicles in the blood of pregnant mice increased markedly throughout pregnancy, while concentrations of extracellular vesicles in the blood of non-pregnant mice remained far lower at corresponding points in time.

In mice under stress, extracellular vesicles decreased at three time points during pregnancy. In a related experiment, researchers treated cultures of human placental cells with the hormone cortisol—produced in response to stress—and the concentration of extracellular vesicles in the cultures also decreased.

The gene for OGT is on the X chromosome, so the placentas of female mouse embryos produce twice as much OGT as male mouse embryos. In another experiment, the researchers estimated the amount of OGT produced in female mice, based on their proportion of female embryos, male embryos, and embryos lacking the gene for OGT. Pregnancies producing the highest total amounts of OGT had the highest concentrations of extracellular vesicles.

Circulating extracellular vesicle (EV) concentrations significantly change in response to altered metabolic state

(A) EV concentration in circulation significantly changes over the course of the day (one-way ANOVA, main effect of time, F_3,13 = 3.509, p = 0.0463). 0700 shown in black, n = 4; 1100 in green, n = 5; 1500 in yellow, n = 4; 1900 in gray, n = 4. (B) The concentration of circulating EVs decreases over the course of the day (left y-axis, black, one-way ANOVA, main effect of time, F_3,13 = 3.509, p = 0.0463), while corticosterone levels increase over the course of the day (right y-axis, red, one-way ANOVA, main effect of time, F_3,13 = 25.62, p < 0.0001). (C) The size of circulating EVs significantly changes over the course of the circadian rhythm (one-way ANOVA, main effect of time, F_3,13 = 8.454, p = 0.0023), and (D) the ζ-potential is significantly changed (one-way ANOVA, main effect of time, F_3,13 = 5.023, p = 0.0158). (E,F) IP injections of corticosterone (red, n = 5) trend to decrease EV concentration in non-pregnant dams as compared to vehicle injections (blue, n = 5, two-tailed t-test, t₈ = 1.351, p = 0.2137). Corticosterone injections did not impact (G) size (two-tailed t-test, t₈ = 1.351, p = 0.2137) or (H) ζ-potential of circulating EVs (two-tailed t-test, t₈ = 0.2309, p = 0.8232). (I) Non-pregnant dams received either no injection (n = 4), vehicle injection (saline, n = 5), 6 h fasting with a vehicle injection (n = 5), 6 h fasting with a glucose injection (3 mg glucose/g body weight, n = 6), or 6 h fasting with an insulin injection (0.8 mU insulin/g body weight, n = 5). There was a significant effect of injection on concentration (one-way ANOVA, main effect of treatment, F_4,20 = 4.883, p = 0.0065) and (J) size (one-way ANOVA, main effect of treatment, F_4,20 = 4.764, p = 0.0073) of circulating EVs but not on (K) ζ-potential of circulating EVs.

In mice as well as in human pregnancies, the ability of the maternal circulation to absorb glucose declines in late pregnancy. Mouse pregnancies having the highest total OGT scores also had the highest concentrations of extracellular vesicles. Although the ability to absorb glucose declined for all the pregnant mice, it declined least for mice having the highest number of extracellular vesicles. The researchers theorized that a rise in OGT and in extracellular vesicles may compensate for the diminished ability to process glucose in late pregnancy.

Significance

The results suggest that placental OGT and extracellular vesicles may play a role in regulating glucose in pregnancy. Similarly, the decline in extracellular vesicles they observed in response to stress, or the stress hormone cortisol, may account for the adverse effects associated with maternal stress during pregnancy, such as preterm birth, gestational diabetes, and preeclampsia.

Source – National Institute of Child Health and Human Development