Intrauterine Growth Restriction and Shallower Implantation Site in Rats with Maternal Hyperinsulinemia are Associated with Altered NOS Expression

Skarzinski, Galina; Khamaisi, Mogher; Bursztyn, Michael; Mekler, Judith; Lan, Dan; Evdokimov, P.; Ariel, Ilana

doi:10.1016/j.placenta.2009.07.014

Cited by 27 publications

(17 citation statements)

References 40 publications

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“…Interestingly a family history of recurrent gestational diabetes was associated with SPTB-PPROM, albeit with wide confidence intervals. It is tempting to speculate that the presence of the insulin resistance syndrome would explain these associations [41], [42]. This may also explain the risk associated with hormonal fertility treatment, but again one would typically expect a clear association with the use of clomiphene; an association not demonstrable in this dataset.…”

Section: Discussionmentioning

confidence: 76%

Risk Factors for Preterm Birth in an International Prospective Cohort of Nulliparous Women

et al. 2012

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ObjectivesTo identify risk factors for spontaneous preterm birth (birth <37 weeks gestation) with intact membranes (SPTB-IM) and SPTB after prelabour rupture of the membranes (SPTB-PPROM) for nulliparous pregnant women.DesignProspective international multicentre cohort.Participants3234 healthy nulliparous women with a singleton pregnancy, follow up was complete in 3184 of participants (98.5%).ResultsOf the 3184 women, 156 (4.9%) had their pregnancy complicated by SPTB; 96 (3.0%) and 60 (1.9%) in the SPTB-IM and SPTB-PPROM categories, respectively. Independent risk factors for SPTB-IM were shorter cervical length, abnormal uterine Doppler flow, use of marijuana pre-pregnancy, lack of overall feeling of well being, being of Caucasian ethnicity, having a mother with diabetes and/or a history of preeclampsia, and a family history of low birth weight babies. Independent risk factors for SPTB-PPROM were shorter cervical length, short stature, participant’s not being the first born in the family, longer time to conceive, not waking up at night, hormonal fertility treatment (excluding clomiphene), mild hypertension, family history of recurrent gestational diabetes, and maternal family history of any miscarriage (risk reduction). Low BMI (<20) nearly doubled the risk for SPTB-PPROM (odds ratio 2.64; 95% CI 1.07–6.51). The area under the receiver operating characteristics curve (AUC), after internal validation, was 0.69 for SPTB-IM and 0.79 for SPTB-PPROM.ConclusionThe ability to predict PTB in healthy nulliparous women using clinical characteristics is modest. The dissimilarity of risk factors for SPTB-IM compared with SPTB-PPROM indicates different pathophysiological pathways underlie these distinct phenotypes.Trial RegistrationACTR.org.au ACTRN12607000551493

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Section: Discussionmentioning

confidence: 76%

Risk Factors for Preterm Birth in an International Prospective Cohort of Nulliparous Women

et al. 2012

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“…Although maternal insulin has been reported not to cross the placental barrier to reach the fetus, excessive amounts of insulin in maternal circulation can alter placental gene expression to affect growth and function of placenta (9). Khamaisi et al (21) and Skarzinski et al (40) reported altered expression of endothelin-converting enzyme-1 and nitric oxide synthase expression in the placenta of hyperinsulinemic dams compared with normal pregnant dams and found an association between these alterations in the placental gene expression and intrauterine growth restriction in rats with maternal hyperinsulinemia. In accord with these findings, elevated insulin concentrations in LIRKO dams could result in various alterations in the placenta to influence fetal growth and development.…”

Section: Discussionmentioning

confidence: 99%

Maternal insulin resistance and transient hyperglycemia impact the metabolic and endocrine phenotypes of offspring

Kahraman

Dirice

Jesus

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Studies in both humans and rodents suggest that maternal diabetes leads to a higher risk of the fetus developing impaired glucose tolerance and obesity during adulthood. However, the impact of hyperinsulinemia in the mother on glucose homeostasis in the offspring has not been fully explored. We aimed to determine the consequences of maternal insulin resistance on offspring metabolism and endocrine pancreas development using the LIRKO mouse model, which exhibits sustained hyperinsulinemia and transient increase in blood glucose concentrations during pregnancy. We examined control offspring born to either LIRKO or control mothers on embryonic days 13.5, 15.5, and 17.5 and postpartum days 0, 4, and 10. Control offspring born to LIRKO mothers displayed low birth weights and subsequently rapidly gained weight, and their blood glucose and plasma insulin concentrations were higher than offspring born to control mothers in early postnatal life. In addition, concentrations of plasma leptin, glucagon, and active GLP-1 were higher in control pups from LIRKO mothers. Analyses of the endocrine pancreas revealed significantly reduced ␤-cell area in control offspring of LIRKO mothers shortly after birth. ␤-Cell proliferation and total islet number were also lower in control offspring of LIRKO mothers during early postnatal days. Together, these data indicate that maternal hyperinsulinemia and the transient hyperglycemia impair endocrine pancreas development in the control offspring and induce multiple metabolic alterations in early postnatal life. The relatively smaller ␤-cell mass/area and ␤-cell proliferation in these control offspring suggest cell-autonomous epigenetic mechanisms in the regulation of islet growth and development. maternal insulin resistance; intrauterine environment; offspring metabolism; endocrine pancreas development; hyperinsulinemia MATERNAL METABOLIC STATUS DURING PREGNANCY is important for fetal growth and development, since the fetus is completely dependent upon its mother for nutrition. Studies have reported that adverse experiences during fetal life can impair fetal development and cause permanent metabolic adaptations in the offspring that would influence their long-term health by increasing the risk for developing insulin resistance, type 2 diabetes, obesity, and/or cardiovascular disease in adulthood (8). To understand the role of intrauterine environment on fetal growth and development, investigators have used various animal models of maternal overnutrition [obesity (29), high-fat diet (15)] and maternal malnutrition (low-protein diet, lowenergy diet) (11) and have also investigated other conditions affecting mothers during pregnancy [e.g., gestational diabetes (34), hyperglycemia (16), hypoxia (46), anemia (24), and glucocorticoid exposure (23)] (2). However, the effects of insulin resistance on a background of transient hyperglycemia in the mother on alterations in metabolism and pancreas development in the offspring remain unclear.Insulin resistance contributes to a range of serious health p...

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“…The iNOS is distributed in arteriolar smooth muscle and the venous endothelium of umbilical vessels, and eNOS is present in the endothelial cells of umbilical and chorionic vessels [23][24][25][26]. In rats, a major expression site of iNOS is the interstitial and endovascular trophoblasts in the mesometrial triangle, and eNOS is found in the endothelium of fetal vessels of the placenta [27]. These reports indicate that NOS enzymes can be produced from smooth muscle or epithelial cells in the developing placental vessels, probably in association with vascular dilation or angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Expression and Localization of NO Synthase Isoenzymes (iNOS and eNOS) in Development of the Rabbit Placenta

Khan

Kusakabe

Wakitani

et al. 2012

Journal of Reproduction and Development

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Abstract. Nitric oxide synthase (NOS) is a key regulator of angiogenesis and embryogenesis in the mammalian reproductive process. Here, we attempted to clarify the expression and localization of inducible and endothelial NOS (iNOS and eNOS) in the developing rabbit placenta. Real-time RT-PCR analysis indicated that iNOS mRNA was significantly upregulated till the complete development of the placenta (d18), and then significantly decreased at the end of fetal growth stage (d28) during successful pregnancy. The eNOS mRNA was also enhanced in the pregnant uteri and gradually decreased near the term of pregnancy. Western blot analysis also showed elevation of the iNOS and eNOS protein levels during the course of successful pregnancy till the functional maturation of the placenta (d18). Immunohistochemical study revealed distinct localizations of iNOS along the radial arteries and eNOS at the spiral arteries and arterial sinuses in the developing placenta. This may reflect that iNOS and eNOS participate in pregnancy success through placentation-specific vascular formation and by supporting adequate blood circulation in the rabbit placenta. Key words: eNOS, iNOS, Rabbit placenta, Vascular formation (J. Reprod. Dev. 58: [231][232][233][234][235][236] 2012) I n pregnant mammals, the placenta acts as exchange interface for nutrients and waste products between the fetal and maternal circulation. The placenta is a very fast growing tissue with corresponding high metabolic demand from the embryo or fetus that requires an active blood supply and rapid vascular development [1][2][3]. Failure of placental growth during early and mid pregnancy is directly associated with inadequate uterine and umbilical blood flow, which adversely affects transportation of fetal nutrients [4]. Extensive increase of the transplacental exchange during the last half of gestation is closely dependent upon the dramatic growth of the vascular architecture and the resultant large volume of uterine and umbilical blood flow [1].Nitric oxide (NO), a multifunctional biomolecule, is produced from the essential amino acid L-arginine via nitric oxide synthase (NOS), which is classified into the calcium-independent or constitutive calcium/calmodulin-sensitive isoforms. The former is represented by inducible NOS (iNOS), and the latter is represented by the endothelial and neuronal NOS (eNOS and nNOS) [5]. NO plays crucial roles in the mediation of a wide variety of physiological processes including vasodilation, angiogenesis, platelet aggression, immune functions, connective tissue remodeling and smooth muscle activity [6]. iNOS and eNOS are known to dynamically regulate normal physiological events during successful pregnancy such as ovulation, implantation, trophoblast invasion, placental formation, fetal development and delivery [7][8][9].In the developing placenta, specific vascular formation occurs through the processes of destruction of preexisting vessels, de novo angiogenesis and convergence of blood path in association with the invitation of plenty ...

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Intrauterine Growth Restriction and Shallower Implantation Site in Rats with Maternal Hyperinsulinemia are Associated with Altered NOS Expression

Cited by 27 publications

References 40 publications

Risk Factors for Preterm Birth in an International Prospective Cohort of Nulliparous Women

Risk Factors for Preterm Birth in an International Prospective Cohort of Nulliparous Women

Maternal insulin resistance and transient hyperglycemia impact the metabolic and endocrine phenotypes of offspring

Expression and Localization of NO Synthase Isoenzymes (iNOS and eNOS) in Development of the Rabbit Placenta

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