RM change in the level of angiogenesis

is one of the most common abnormalities associated with pregnancy, which in
many cases the cause remains unknown. Studies have shown that defects in the
phenomenon of angiogenesis can lead to this disorder (21). In this
phenomenon, different genes are involved, in which their aberrant expression
can lead to a change in the level of angiogenesis and the delivery of nutrient
to the fetus, consequently, fetus may be aborted (17, 21). In 2016, Zhu
and colleagues analyzed the inhibitory effect of miR-16 on feto-maternal
angiogenesis and recurrent spontaneous abortion, and its association with the expression
of VEGF-A in samples of the villi, decidua, and trophoblast cell lines, and showed
that the miR-16 expression was higher in the villi and decidua, and the direct
target of miR-16 is VEGF-A (19). However, the
expression of these genes in blood samples of the patients has not been studied.

we examined the expression of miR-16 and VEGF-A in both plasma and PBMCs and found
that although higher expression level of miR-16 in the plasma of uRM group compared
with the control group, it was not significant but in PBMCs, its expression
level was statistically significant. Also, in these cells, expression level of VEGF-A
in the uRM group was more than P <.05. Thus, it can be concluded that there is no significant relationship between miR-16 and VEGF-A in mRNA levels. This result was incompatible with the study of Amirchaghmaghi et al, which was carried out at the protein level. (22). It is possible that this relationship exists only at the levels of protein expression. In another investigation, we studied the expression of miR-21 and PTEN in PBMCs and showed that there is a correlation between their expression levels, so that miR-21 and PTEN in women with uRM was downregulated and upregulated, respectively. These findings were consistent with the study by Tokyol et al in 2008, that showed a remarkable increase in the expression of PTEN in decidua and trophoblast cells of patients with RM (23). Also, plasma examination of these patients revealed a decrease in miR-21 expression, which was similar to the findings of El-Shorafa et al (24). Considering that investigations has shown that embryo development is associated with similar mechanisms with tumor invasion (16), there is a possibility for involvement  of these genes in maternal angiogenesis. In 2011, a study conducted to examine the effect of miR-21 on human tumor cells demonstrated that with increasing the expression of this miRNA, Akt/Erk signaling pathways are activated, that leading to increased expression of HIF-1? and VEGF, and  also enhances angiogenesis (20). In recurrent miscarriage, the angiogenesis can occur inversely, which means that by reducing the angiogenesis, nutrient delivery to the fetus is reduced and miscarriage may takes place. Although in our study, the VEGF-A expression was not significantly altered, but in accordance with studies performed (22, 25), it is likely that its expression at the protein level will be significant. Therefore, further research is needed in this regard and our proposed model in associated with this study is as follows:

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