Article Review 4

CXCR4, CXCR7, and CXCL12 Are Associated with Trophoblastic Cells Apoptosis and Linked to Pathophysiology of Severe Preeclampsia

The purpose of this paper was to examine the expression of the chemokine CXCL12 and its receptors, CXCR4 and CXCR7, in placental tissues and primary trophoblasts from preeclamptic and normal pregnancies. CXCL12 and its receptors are involved not only in the immune system, but also in various other processes, including remodeling the spiral arteries to form the placenta. CXCL12 and CXCR4 have been shown to be involved in trophoblast proliferation and invasion and decidual stromal cell migration and motility; lack of either of these functions is associated with preeclampsia. The authors examined the association between these proteins and preeclampsia.

Placentas were obtained after a cesarean section (21 normal pregnant, 11 mild preeclamptic, and 18 severe preeclamptic). A scanning electron microscope was used to observe morphological changes of trophoblast cells in preeclamptic placentas that caused a significant tendency towards apoptosis. Immunohistochemistry showed that there were lower levels of CXCR4, CXCR7, and CXCR12 were lower in severe preeclamptic placentas than in normal placentas. RT-qPCR was used to show that the same pattern was true for mRNA expression of the proteins, and Western blot analysis confirmed for protein expression levels in trophoblasts. The authors concluded that apoptosis of the cytotrophoblast cells may be regulated by expression of CXCR4, CXCR7, and CXCL12.

All three proteins have been shown to be important for proper placenta formation, so I think the research to compare expression between normal and preeclamptic patients is necessary and relevant. I think the study was well designed, especially by using different techniques to confirm results. However, the number of samples was small, only 50 in total, probably because the placenta was required for testing.

It would be interesting to see if the results in this study were replicated in a future study with more samples. While the study observes a decrease in the three proteins studied, more studies are required to understand the how they relate to the pathophysiology of preeclampsia. Additional studies should be done to understand the mechanism of cytotrophoblast invasion and how CXCL12 and its receptors relate to this.


Lu, Jing, et al. “CXCR4, CXCR7, And CXCL12 Are Associated With Trophoblastic Cells Apoptosis And Linked To Pathophysiology Of Severe Preeclampsia.” Experimental And Molecular Pathology 100. (2016): 184-191. ScienceDirect. Web. 9 Oct. 2016.


Article Review 3

An RGS2 3’UTR Polymorphism is Associated With Preeclampsia in Overweight Women

Preeclampsia is a pregnancy-associated syndrome initiated by poor placental perfusion which, together with maternal genetic and metabolic risk factors, cause the maternal response. The regulation of G-protein signaling 2 (RGS2) gene has been implicated in blood pressure regulation by inhibiting vasoconstriction mediated by G protein-coupled receptors. Low RGS2 levels is associated with hypertension and obesity. One cause of low RGS2 levels is the 3’ UTR C1114G polymorphism in the RGS2 gene (mutation rs4606). This study used obstetric and perinatal data to classify pregnancies as preeclamptic or normal control and as normal, overweight, or obese based on the mother’s pre-pregnancy body mass index. The rs4606 mutation was in Hardy-Weinberg equilibrium, though no association between preeclampsia and the rs4606 mutation was found under a dominant, recessive, or additive model. However, the CG and GG genotypes were significantly associated with preeclampsia in overweight women. The researchers concluded that RGS2 function could contribute to the increased rate of preeclampsia in overweight women.

All of the study participants had extensive clinical background information available for admission into the study and for classification of the pregnancies. Since the study included women from all Finnish university hospitals, the participants were representative of the Finnish population. The critical value for the statistical tests was 0.05, which is generally accepted as statistically significant data. Additionally, over 1300 preeclamptic and 600 normal pregnancies were included in the study, which is a decent size.

The rs4606 mutation in the RGS2 gene is associated with metabolic syndrome in white European men, weight gain in young hypertensive men, personality traits and brain function linked to anxiety disorders, and lower benefit from sertraline treatment to social anxiety disorder. Therefore, women with the mutation could be at higher risk of postpartum depression in addition to the known cardiovascular and insulin resistance problems after pregnancy. More research should be done to determine the role of RGS2 and the effect of the rs4606 mutation on that role.  Similar studies should include data on participants’ personality traits and anxiety disorders to determine if this mutation could explain some of the link between preeclampisa and anxiety/depression.

Karppanen, Tina, et al. “An RGS2 3’UTR Polymorphism is Associated With Preeclampsia in Overweight Women.” BMC Genetics 17. (2016): 1-7. Academic Search Complete. Web. 9 Oct. 2016.

Article Review 1

Preeclampsia is characterized by new onset hypertension and proteinuria after 20 weeks gestation.  Though the pathophysiology has not been fully defined, preeclampsia is thought to begin when the fetal trophoblastic cells and maternal endothelial cells fail to adequately remodel to supply blood to the fetus.  This placental ischemia results in the release of maternal factors such as cytokines – those studied in this paper are adiponectin and leptin.  Both of these are released by white adipose tissue and, during pregnancy, are involved in trophoblastic invasion.  These cytokines are mediated by metalloproteinases (MMPs) such as MMP2 and MMP9 and their inhibitors (TIMP1 and TIMP2).

In this study, adiponectin, leptin, MMP2, MMP9, TIMP1, and TIMP2 plasma concentrations were compared between healthy pregnancies and preeclamptic pregnant groups.  ELISA kits were used to measure the concentrations and Student’s t-test, the chi-squared test, and the Pearson’s correlation test were performed on the data.  Maternal age, BMI, MMP9 levels, MMP9/TIMP1 and MMP2/TIMP2 ratios were not statistically different from each other.  Both systolic and diastolic blood pressure were higher, and gestational age at sampling, delivery, and newborn weight were lower in the preeclamptic group compared to the HP group. Leptin, adiponectin, TIMP1, TIMP2, and MMP2 were higher in the preeclamptic group as well.

I think the paper is relevant and the experimental approach is sound.  The significance point for the data is P<0.05, which is not different from many other papers published in various journals.  The paper’s authors say comment that, to their knowledge, “This is the first study to measure correlation between circulating adiponectin and leptin and MMP/TIMP concentrations in preeclamptic patients, even though both have been shown to be related to trophoblast invasion” (Eleuterio, et al. 2015).  The results show that the study is relevant and matches the stated objective of the paper in the abstract.  All the cytokines and metalloproteinases measured were higher in preeclamptic patients, showing that, clearly, the study was needed.

Future studies could either block the production or interfere with the activity of adiponectin, leptin, or the metalloproteinases in animal models of preeclampsia or in endothelial cell cultures.  These studies could monitor the effects on the other cytokines and proteinases or on the symptoms such as placental ischemia.  The authors also suggested that adiponectin may contribute to higher levels of MMP2 and TIMP2, so studies could be done to elucidate that relationship.

Works Cited

Eleuterio, Nibia Mariana, et al.  “Positive Correlations Between Circulating Adiponectin and MMP2 in Preeclampsia Pregnant.”  Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 5. (2015): 205-208.  ScienceDirect.  Web.  9 Sept. 2016.