Modeling the impact of growth and leptin deficits on the neuronal regulation of blood pressure

The risk of hypertension is increased by intrauterine growth restriction (IUGR) and preterm birth. In the search for modifiable etiologies for this life-threatening cardiovascular morbidity, a number of pathways have been investigated, including excessive glucocorticoid exposure, nutritional deficiency and aberration in sex hormone levels. As a neurotrophic hormone that is intimately involved in the cardiovascular regulation and whose levels are influenced by glucocorticoids, nutritional status and sex hormones, leptin has emerged as a putative etiologic and thus a therapeutic agent. As a product of maternal and late fetal adipocytes and the placenta, circulating leptin typically surges late in gestation and declines after delivery until the infant consumes sufficient leptin-containing breast milk or accrues sufficient leptin-secreting adipose tissue to reestablish the circulating levels. The leptin deficiency seen in IUGR infants is a multifactorial manifestation of placental insufficiency, exaggerated glucocorticoid exposure and fetal adipose deficit. The preterm infant suffers from the same cascade of events, including separation from the placenta, antenatal steroid exposure and persistently underdeveloped adipose depots. Preterm infants remain leptin deficient beyond term gestation, rendering them susceptible to neurodevelopmental impairment and subsequent cardiovascular dysregulation. This pathologic pathway is efficiently modeled by placing neonatal mice into atypically large litters, thereby recapitulating the perinatal growth restriction–adult hypertension phenotype. In this model, neonatal leptin supplementation restores the physiologic leptin surge, attenuates the leptin-triggered sympathetic activation in adulthood and prevents leptin- or stress-evoked hypertension. Further pathway interrogation and clinical translation are needed to fully test the therapeutic potential of perinatal leptin supplementation.

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152 Impact of chorionic somatomammotropin RNA interference on uterine blood flow and placental glucose uptake in the absence of intrauterine growth restriction

Journal of Animal Science ◽

10.1093/jas/skaa278.220 ◽

2020 ◽

Vol 98 (Supplement_4) ◽

pp. 121-121

Author(s):

Amelia R Tanner ◽

Asghar Ali ◽

Quinton A Winger ◽

Paul J Rozance ◽

Russell V Anthony

Keyword(s):

Rna Interference ◽

Glucose Uptake ◽

Intrauterine Growth Restriction ◽

Growth Restriction ◽

Intrauterine Growth ◽

Blood Flows ◽

Umbilical Blood ◽

Exact Function ◽

Chorionic Somatomammotropin ◽

The Impact

Abstract Chorionic somatomammotropin (CSH) is one of the most abundant hormones produced by the sheep placenta, yet the exact function of CSH has been elusive. Previously we reported the use of in vivo RNA interference (RNAi) to assess the impact of CSH deficiency on placental and fetal growth in sheep. Near-term (135 dGA), there are two distinct CSH RNAi phenotypes: 1) pregnancies with intrauterine growth restriction (IUGR), and 2) pregnancies with normal fetal and placental weights. This study describes physiological changes in the latter phenotype. To generate the CSH RNAi pregnancies, the trophectoderm of hatched blastocysts (9 dGA) were infected with lentiviral-constructs expressing either a scrambled control (NTS) or CSH-specific shRNA (CSH RNAi), prior to transfer into synchronized recipient ewes. At 120 dGA, 6 NTS and 6 CSH RNAi pregnancies were fitted with maternal and fetal catheters. Uterine and umbilical blood flows were measured utilizing the 3H2O transplacental diffusion technique at 132 dGA, and nutrient uptakes were calculated by the Fick principle. Resulting data were analyzed by Student’s t-test and significance was set at P ≤ 0.05. CSH RNAi tended (P ≤ 0.10) to reduce placentome weight with no effect on fetal weight. Absolute (ml/min) and relative (ml/min/kg fetus) uterine blood flows were reduced (P ≤ 0.05) in CSH RNAi pregnancies, but umbilical flows were not impacted. The uterine artery-to-vein glucose gradient (mmol/l) was significantly (P ≤ 0.05) increased, whereas the gradients for taurine and glycine were reduced (P ≤ 0.05). Uteroplacental glucose uptake (mmol/min/kg placenta) was increased 27% (P ≤ 0.05), whereas umbilical glucose uptake (mmol/min/kg fetus) was reduced 13%. This cohort demonstrates that even in the absence of IUGR, CSH deficiency has significant physiological ramifications, and the investigation of CSH RNAi pregnancies exhibiting both IUGR and non-IUGR phenotypes may help determine the direct effects of CSH and its potential impact on fetal programming. Supported by NIH R01 HD093701.

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Whey Versus Casein as a Protein Source during the Weaning Period: Impact on Growth and Later Adiposity and Glucose Homeostasis in a Rat Model of Intrauterine Growth Restriction

Nutrients ◽

10.3390/nu12113399 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3399

Author(s):

Yasaman Shahkhalili ◽

Florence Blancher-Budin ◽

Cathriona Monnard ◽

Julie Moulin ◽

José Sanchez-Garcia ◽

...

Keyword(s):

Glucose Homeostasis ◽

Intrauterine Growth Restriction ◽

Early Life ◽

Growth Restriction ◽

Protein Source ◽

Intrauterine Growth ◽

Populations At Risk ◽

Ad Libitum ◽

The Impact

The impact of early life protein source (whey vs. casein) on short- and long-term glucose homeostasis and adiposity is unknown and was investigated in this study. At the end of the suckling period, non-IUGR (intrauterine growth restriction) and IUGR pups were separated from dams and were randomized into four groups. From age 21–49 days, non-IUGR and IUGR pups were fed ad-libitum chow or a semi-synthetic diet (20% from protein; casein or whey) and from age 50–199 days, all groups were fed ad-libitum chow. Food intake, body composition, glucose, and insulin homeostasis were assessed. Among the chow groups, IUGR had slower growth and higher fasting glucose at age 42 days, as well as higher fasting and AUC glucose at age 192 days relative to non-IUGR. The whey IUGR group had a slower growth rate and higher fasting glycemia in early life (age 21–49 days) and higher HOMA-IR later in life (age 120–122 and 190–192 days) relative to casein IUGR. This study shows the potential advantage of casein relative to whey during weaning on short term energy intake, growth, and glucose homeostasis in an IUGR model and reveals, for the first time, its long term impact on insulin sensitivity, which may have implications for later metabolic health, particularly in small-for-gestational-age populations at risk of type 2 diabetes.

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Vitamin D deficiency and impaired placental function: potential regulation by glucocorticoids?

Reproduction ◽

10.1530/rep-16-0647 ◽

2017 ◽

Vol 153 (5) ◽

pp. R163-R171 ◽

Cited By ~ 13

Author(s):

Nathanael Yates ◽

Rachael C Crew ◽

Caitlin S Wyrwoll

Keyword(s):

Vitamin D ◽

Vitamin D Deficiency ◽

Intrauterine Growth Restriction ◽

Adverse Outcomes ◽

Growth Restriction ◽

Placental Function ◽

Maternal Vitamin ◽

Intrauterine Growth ◽

The Impact ◽

Established Role

Maternal vitamin D deficiency has been implicated in a range of pregnancy complications including preeclampsia, preterm birth and intrauterine growth restriction. Some of these adverse outcomes arise from alterations in placental function. Indeed, vitamin D appears critical for implantation, inflammation, immune function and angiogenesis in the placenta. Despite these associations, absence of the placental vitamin D receptor in mice provokes little effect. Thus, interactions between maternal and fetal compartments are likely crucial for instigating adverse placental changes. Indeed, maternal vitamin D deficiency elicits changes in glucocorticoid-related parameters in pregnancy, which increase placental and fetal glucocorticoid exposure. Asin uteroglucocorticoid excess has a well-established role in eliciting placental dysfunction and fetal growth restriction, this review proposes that glucocorticoids are an important consideration when understanding the impact of vitamin D deficiency on placental function and fetal development.

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The impact of intrauterine growth restriction on cytochrome P450 enzyme expression and activity

Placenta ◽

10.1016/j.placenta.2020.07.012 ◽

2020 ◽

Vol 99 ◽

pp. 50-62

Author(s):

Grace M. McBride ◽

Michael D. Wiese ◽

Jia Yin Soo ◽

Jack R.T. Darby ◽

Mary J. Berry ◽

...

Keyword(s):

Cytochrome P450 ◽

Intrauterine Growth Restriction ◽

Growth Restriction ◽

Cytochrome P450 Enzyme ◽

Enzyme Expression ◽

Intrauterine Growth ◽

P450 Enzyme ◽

The Impact ◽

Expression And Activity

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The impact of maternal parameters on intrauterine growth restriction

Perinatologia ◽

10.26416/peri.1.1.2017.470 ◽

2017 ◽

Vol 1 (1) ◽

pp. 6

Author(s):

Monica Mihaela Cîrstoiu ◽

Natalia Turcan ◽

Roxana-Elena Bohîlţea ◽

Octavian Munteanu ◽

Oana Bodean ◽

...

Keyword(s):

Intrauterine Growth Restriction ◽

Growth Restriction ◽

Intrauterine Growth ◽

The Impact

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The effect of hypoxia-induced intrauterine growth restriction on renal artery function

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174412000268 ◽

2012 ◽

Vol 3 (5) ◽

pp. 333-341 ◽

Cited By ~ 6

Author(s):

M. T. C. Verschuren ◽

J. S. Morton ◽

A. Abdalvand ◽

Y. Mansour ◽

C. F. Rueda-Clausen ◽

...

Keyword(s):

Renal Artery ◽

Intrauterine Growth Restriction ◽

Vascular Function ◽

In Utero ◽

Growth Restriction ◽

Dependent Manner ◽

Intrauterine Growth ◽

Kidney Morphology ◽

Renal Senescence ◽

The Impact

The risk of developing cardiovascular diseases is known to begin before birth and the impact of the intrauterine environment on subsequent adult health is currently being investigated from many quarters. Following our studies demonstrating the impact of hypoxiain uteroand consequent intrauterine growth restriction (IUGR) on the rat cardiovascular system, we hypothesized that changes extend throughout the vasculature and alter function of the renal artery. In addition, we hypothesized that hypoxia induces renal senescence as a potential mediator of altered vascular function. We demonstrated that IUGR females had decreased responses to the adrenergic agonist phenylephrine (PE; pEC506.50 ± 0.05 controlv. 6.17 ± 0.09 IUGR,P< 0.05) and the endothelium-dependent vasodilator methylcholine (MCh;Emax89.8 ± 7.0% controlv. 41.0 ± 6.5% IUGR,P< 0.001). In IUGR females, this was characterised by increased basal nitric oxide (NO) modulation of vasoconstriction (PE pEC506.17 ± 0.09 IUGRv. 6.42 ± 0.08 in the presence of the NO synthase inhibitorN-nitro-l-arginine methyl ester hydrochloride (l-NAME;P< 0.01) but decreased activated NO modulation (no change in MCh responses in the presence ofl-NAME), respectively. In contrast, IUGR males had no changes in PE or MCh responses but demonstrated increased basal NO (PE pEC506.29 ± 0.06 IUGRv. 6.42 ± 0.12 plusl-NAME,P< 0.01) and activated NO (Emax37.8 ± 9.4% controlv. −0.8 ± 13.0% plusl-NAME,P< 0.05) modulation. No significant changes were found in gross kidney morphology, proteinuria or markers of cellular senescence in either sex. In summary, renal vascular function was altered by hypoxiain uteroin a sex-dependent manner but was unlikely to be mediated by premature renal senescence.

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Are Fetal and Neonatal Growth Curves Different in Predicting the Impact of Intrauterine Growth Restriction on Neonatal Mortality and Morbidity?

Pediatric Research ◽

10.1203/00006450-199904020-01547 ◽

1999 ◽

Vol 45 (4, Part 2 of 2) ◽

pp. 260A-260A

Author(s):

W Zaw ◽

R Gagnon ◽

V Capewell ◽

O P da Silva

Keyword(s):

Neonatal Mortality ◽

Intrauterine Growth Restriction ◽

Growth Curves ◽

Growth Restriction ◽

Mortality And Morbidity ◽

Intrauterine Growth ◽

Neonatal Growth ◽

The Impact

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Maternal and Placental Risk Factors associated with Intrauterine Growth Restriction and the Perinatal Outcomes

Journal of SAFOG with DVD ◽

10.5005/jp-journals-10006-1351 ◽

2015 ◽

Vol 7 (3) ◽

pp. 176-181 ◽

Cited By ~ 1

Author(s):

Valsa CA Thekkedathu

Keyword(s):

Risk Factors ◽

Statistical Analysis ◽

Intrauterine Growth Restriction ◽

Perinatal Outcomes ◽

Growth Restriction ◽

Chronic Hypertension ◽

Maternal Risk ◽

Intrauterine Growth ◽

Factors Associated ◽

The Impact

ABSTRACT Objectives Identifying the factors responsible for the intrauterine growth restriction (IUGR) is very important, so that early interventions could be suggested to improve the perinatal outcome. The major objectives of this study are to analyze the impact of risk factors, specifically the maternal and placental risk factors, on IUGR and the perinatal outcomes. Materials and methods A prospective study was done on 60 women with IUGR pregnancies from January 2013 to January 2014, at Pushpagiri Medical College Hospital, Thiruvalla. Inclusion criteria were: singleton pregnancies, above the gestational age of 28 weeks, clinically diagnosed IUGR and confirmed subsequently on ultrasound. The statistical analysis was performed utilizing Statistical Package of the Social Sciences (SPSS) software and the significance level of p-value < 0.05 was accepted as statistically significant. Results Statistical analysis shows that maternal risk factors like chronic hypertension, pre-eclampsia, low socioeconomic status of mother, overt diabetes, anemia, gestational diabetes mellitus, low prepregnancy body mass index and hypothyroidism were significantly associated with IUGR. In this study, placental factors like chorangiomatosis, increased syncytial knotting, villous infarction, increased perivillous fibrinoid deposition, accelerated villous maturation, retroplacental hemorrhage and acute chorioamnionitis were significantly associated with IUGR. Conclusion Alertness toward antenatal risk factors for poor pregnancy outcome is important for the optimal management of IUGR pregnancies. Despite antenatal recognition of IUGR and associated risk factors, not all perinatal deaths can be prevented. How to cite this article Thekkedathu VCA. Maternal and Placental Risk Factors associated with Intrauterine Growth Restriction and the Perinatal Outcomes. J South Asian Feder Obst Gynae 2015;7(3):176-181.

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Human Leucocyte Antigen G and Murine Qa-2 Are Critical for Myeloid Derived Suppressor Cell Expansion and Activation and for Successful Pregnancy Outcome

Frontiers in Immunology ◽

10.3389/fimmu.2021.787468 ◽

2022 ◽

Vol 12 ◽

Author(s):

Stefanie Dietz ◽

Julian Schwarz ◽

Ana Velic ◽

Irene González-Menéndez ◽

Leticia Quintanilla-Martinez ◽

...

Keyword(s):

Pregnancy Outcome ◽

Immune Cell ◽

Therapeutic Potential ◽

Suppressor Cells ◽

Suppressor Cell ◽

Late Pregnancy ◽

Growth Restriction ◽

Trophoblast Invasion ◽

The Impact

During pregnancy, maternal immune system has to balance tightly between protection against pathogens and tolerance towards a semi-allogeneic organism. Dysfunction of this immune adaptation can lead to severe complications such as pregnancy loss, preeclampsia or fetal growth restriction. In the present study we analyzed the impact of the murine MHC class Ib molecule Qa-2 on pregnancy outcome in vivo. We demonstrate that lack of Qa-2 led to intrauterine growth restriction and increased abortion rates especially in late pregnancy accompanied by a disturbed trophoblast invasion and altered spiral artery remodeling as well as protein aggregation in trophoblast cells indicating a preeclampsia-like phenotype. Furthermore, lack of Qa-2 caused imbalanced immunological adaptation to pregnancy with altered immune cell and especially T-cell homeostasis, reduced Treg numbers and decreased accumulation and functional activation of myeloid-derived suppressor cells. Lastly, we show that application of sHLA-G reduced abortion rates in Qa-2 deficient mice by inducing MDSC. Our results highlight the importance of an interaction between HLA-G and MDSC for pregnancy success and the therapeutic potential of HLA-G for treatment of immunological pregnancy complications.

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