[Placental gene activity of significant angiogenetic factors in the background of intrauterine growth restriction]. / A legjelentosebb angiogeneticus gének méhlepényi expressziójának változásai a méhen belüli növekedési visszamaradás hátterében.

Placental vascular endothelial growth factor A (VEGF-A) gene and endoglin gene are both overexpressed in placental samples obtained from pregnancies with intrauterine growth restriction compared to normal pregnancies. In the background of these changes a mechanism can be supposed, in which the increased endoglin activity in intrauterine growth restriction (IUGR) leads to impaired placental circulation through an antioangiogenetic effect. This results in the development of placental vascular dysfunction and chronic fetal hypoxia. It is chronic hypoxia that turns on VEGF-A as a compensatory mechanism to improve fetal vascular blood supply by promoting placental blood vessel formation. Although the maternal serum placental growth factor (PlGF) level is a potential predictor for both IUGR and praeeclampsia, placental PlGF gene activity may be less of an active in the regulation of placental circulation in IUGR pregnancies during the later stages of gestation. Orv. Hetil., 2017, 158(16), 612-617.

Placental gene expression patterns of endoglin (CD105) in intrauterine growth restriction.

OBJECTIVE: In this study, we describe placental gene expression patterns of endoglin in pregnancies with intrauterine growth restriction (IUGR) compared to normal pregnancies. METHODS: Placental samples were obtained from 101 pregnancies with IUGR using 140 normal pregnancy cases as control. Gene expression patterns and protein levels of the endoglin were compared between the two groups. For the gene expression analysis real-time PCR was applied, while for the estimation of placental protein level we performed Western analysis. RESULTS: The placental endoglin gene was significantly overexpressed in the IUGR group versus the control group (Ln2(α): 1.69). The placental endoglin protein level proved to be significantly higher in case of IUGR (endoglin/ß-actin ratio: 13.8 ± 2.3) versus the control cases (5.3 ± 1.1). The placental gene expression as well as the protein levels of endoglin showed no significant difference between female and male newborns. Concerning the placental gene expression and protein level, no significant difference was justified between the more (0-5 percentile) and less (5-10 percentile) severe cases of IUGR. CONCLUSION: Increased placental gene expression of endoglin may result in vascular dysfunction leading to chronic fetal hypoxia, which may induce VEGF-A to stimulate angiogenesis. This can be explained as feed back response to restore fetal placental circulation.

Placental gene expression patterns of epidermal growth factor in intrauterine growth restriction.

OBJECTIVE: In this study, we compared human placental gene expression patterns of epidermal growth factor (EGF) in pregnancies with intrauterine growth restriction (IUGR) vs. normal pregnancies as control. STUDY DESIGN: Gene expression of EGF was determined from human placental samples collected from all pregnancies presenting with IUGR at our institution during the study period January 1, 2010-January 1, 2011. Multiple clinical variables were also assessed including maternal age, gestational weight gain, increase of BMI during pregnancy and fetal gender. RESULTS: A total of 241 samples were obtained (101 in the IUGR pregnancy group, 140 in the normal pregnancy group). EGF was found to be underexpressed in the IUGR group compared to normal pregnancy (Ln2(α): -1.54; p<0.04). Within the IUGR group no fetal gender-dependent difference was seen in EGF gene expression (Ln2(α): 0.44; p<0.06). Similarly, no significant difference in EGF expression was noted in cases with more vs. less severe forms of IUGR (Ln2(α): -0.08; p=0.05). IUGR pregnancies were significantly more common in the maternal age group 35-44 years compared to other age groups. Gestational weight gain and gestational BMI increase were significantly lower in IUGR pregnancies compared to controls. CONCLUSIONS: Placental expression of EGF was found to be reduced in IUGR pregnancies vs. normal pregnancies. This may partly explain the smaller placental size and placental dysfunction commonly seen with IUGR. An increased incidence of IUGR was observed with maternal age exceeding 35 years. The probability of IUGR correlated with lower gestational weight gain and lower BMI increase during pregnancy.

Gene expression patterns of vascular endothelial growth factor (VEGF-A) in human placenta from pregnancies with intrauterine growth restriction.

OBJECTIVE: In this study, we describe changes in gene expression pattern of vascular endothelial growth factor (VEGF)-A in human placenta obtained from pregnancies with intrauterine growth restriction using placenta from normal pregnancies as control. METHODS: We compared gene expression of VEGF-A in placental samples from Intrauterine growth restriction (IUGR) pregnancies versus placenta obtained from normal pregnancies. Among potential confounders, important clinical informations were also analyzed. RESULTS: In the IUGR group, the VEGF-A gene was overexpressed compared to the normal pregnancy group (Ln 2(α)ß-actin: 1.32; Ln 2(α)GADPH: 1.56). There was no correlation between the degree of growth restriction and VEGF-A gene expression (Ln 2(α)(0-5)percentile: 0.58; Ln 2(α)(5-10)percentile: 0.64). Within the IUGR group, there was a trend toward a positive correlation between placental VEGF-A gene activity and gestational age at delivery (Ln 2(α)< 33 weeks: 1.09; Ln 2(α)33-37 weeks: 1.27; Ln 2(α)> 37 weeks: 1.35). CONCLUSIONS: Our findings suggest that the increase in placental expression of the VEGF-A gene and the resultant stimulation of angiogenesis are a response to hypoxic environment developing in the placental tissue in IUGR. Thus, it appears to be a secondary event rather than a primary factor in the development of IUGR There is a trend toward a positive correlation between gestational age and placental VEGF-A gene activity.

The regulation of apoptosis in intrauterine growth restriction: a study of Bcl-2 and Bax gene expression in human placenta.

OBJECTIVE: In this study, we assessed Bcl-2 and Bax gene expression patterns in human placental samples from intrauterine growth restriction (IUGR) pregnancies using normal pregnancy as control. METHODS: We compared Bcl-2 and Bax gene expression in placental samples from all IUGR pregnancies treated in our clinic between 1 January 2010-1 January 2011 vs. 140 normal pregnancy samples from the same study period. We also assessed clinical parameters such as maternal age, gestational weight gain, gestational body mass index (BMI) change, and maternal birth weight. RESULTS: In IUGR, the Bcl-2 gene was underexpressed compared to normal pregnancy. There was no difference in the Bax gene activity in the two groups. The degree of growth restriction within the IUGR group did not correlate with Bcl-2 or Bax gene activity. CONCLUSIONS: Our study revealed that it is the reduced inhibitory activity of the Bcl-2 gene rather than an enhanced stimulatory activity of the Bax gene in the background of the increased apoptosis observed in IUGR. IUGR appears to be more common with maternal age around 20 years and above 35 years. Gestational weight gain and gestational BMI change also predict the risk for IUGR.

Abnormal fetomaternal glucocorticoid metabolism in the background of premature delivery: placental expression patterns of the 11ß-hydroxysteroid dehydrogenase 2 gene.

OBJECTIVE: During pregnancy, 11ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2) is involved in the development of the placental barrier, and its main function is to protect the fetus from the effects of the physiological increase of maternal glucocorticoids. We compared human placental gene expression patterns of 11ß-HSD2 from pregnancies that ended with preterm delivery versus full term pregnancies as controls. STUDY DESIGN: We used real-time PCR to assess the placental gene expression patterns of 11ß-HSD2 in 104 preterm and 140 full term pregnancies (control group) at the time of delivery. RESULTS: In the preterm delivery group, the proportion of smokers was 26.9%, significantly higher than in the control group. Preterm delivery began with premature rupture of membranes in 70.2% and spontaneous uterine activity in 29.8%. The 11ß-HSD2 gene was underexpressed in the preterm delivery group compared to normal pregnancy between 28 and 36 gestational weeks, but unchanged between 24 and 28 weeks. There was no fetal gender effect on 11ß-HSD2 gene expression. CONCLUSION: The reduced activity of the 11ß-HSD2 gene seen in the preterm delivery group may impair fetal defences against maternal glucocorticoid exposure. In cases of impending premature delivery, glucocorticoid effects, potentially including postnatal neurological abnormalities and growth restriction, may be worsened by prophylactic steroids given to accelerate fetal lung maturity. The impairment in fetal defences against maternal glucocorticoids due to reduced 11ß-HSD2 enzyme activity appears to begin after gestational week 28.