The primary origin of fetal derangements in gestational diabetic mothers is fetal hyperglycaemia resulting from maternal hyperglycaemia. This hyperglycaemia may result in the metabolic and hormonal change in the fetus. Once the fetal pancreas commences to produce and secrete insulin in the second trimester [
23], fetal hyperglycaemia will result in fetal hyperinsulinemia and stimulation of fetal metabolism. Lower fetal oxygen content associated by higher lactate concentrations may certainly reflect enhanced fetal metabolism as a result of hyperglycaemia and hyperinsulinemia [
24]. Consequently, the improvement of fetal oxygen demands will aggravate the chronic fetal hypoxia [
25]. The hyperglycemia of GDM develops during pregnancy and clinically manifests only in the late second trimester and thus may have an impact on placental processes occurring in later stages of pregnancy, such as angiogenesis and microvascular remodeling. VEGF/VEGFR-2, which was selected as representative factors related to the placental blood barrier and angiogenesis in this study, is important in promoting vascular endothelial cell growth and in increasing the number of vessels and capillaries [
22], thereby ensuring the adequate supply of nutrients to the fetus, through classical feedback mechanism. We found that the expressions of VEGFA and VEGFR2 was significantly lower in the placentas of women with GDM although we did not show the relationship between above expressions and the increased glucose levels or abnormal levels in their OGTTs due to the limited sample size. There is consistent evidence that the concentration of VEGF in GDM maternal and cord plasma was decreased [
26]. VEGF mRNA expression and protein production are oxygen-dependent, which are known to be up-regulated by hypoxia [
27]. Just because of the strong proangiogenic potency of hypoxia through regulating multiple steps of vascular growth [
28], chronic fetal hypoxia as the consequence of maternal diabetes may thus stimulate placental vasculogenesis and angiogenesis by increasing the growth factors expression in the placenta and fetus. Parallel to its regulation by oxygen, placental VEGF is at a high level in the first trimester when oxygen levels are low and decline thereafter towards term of gestation [
29‐
31], moreover the extent of hyperglycemia other than hypoxia may also contribute and modify its effect [
32]. Thus, the condition of hyperglycemia induces a state of mild and persistent ischemia and hypoxia with subsequent increase of hypercapillarization. In contrast, high blood glucose levels especially poorly controlled in GDM trigger severe hypoxia/ischemia, with inhibition of binding VEGF/VEGFR-2 and consequent reduction of hypercapillarization, and therefore fetal hypoxia as a result of maternal diabetes does not stimulate the expression of VEGF in the third trimester [
33]. The complex process of villous development and maturity might be also influenced by the maternal and fetal oxidative and other angiogenetic milieu, which will result in endothelial dysfunction and oxidative stress [
34]. As the placenta is one of major sources of VEGF during pregnancy, our findings suggested that the reduced expression of VEGF in placenta in the GDM group may contribute to the pathogenic vascular defects which could be observed on the histological examination. Two other studies have also reported that the placental expression and fetal cord levels in GDM are significantly lower than normal [
32
35].
These data were confirmed by immunolocalization of VEGF and VEGFR-2. The distribution of VEGF was observed in the placentas of women with GDM, and no VEGF was detected in the placental cellular compartments, which suggested a decrease in VEGF production. VEGF was always detected in the in the ST layer of term control tissues and term GDM tissues [
32], in women with gestational diabetes there was a significant decrease in VEGF expression profile when compared to normoglycemic women. The target cells for VEGF in the chorionic villi were determined based on the immunolocalization of VEGFR-2, which expression was particularly low in the placental capillary endothelial cells of gestational diabetes, in contrast to normoglycemic women. The binding between VEGF and VEGFR-2 triggers a signaling pathway that negatively regulates angiogenesis.
Our finding showed that distinct alternations of ultrastructure in GDM placenta comparing with control placenta. The significant differences in ultrastructure may be summarized as the thickening of the vasculo-syncytial membrane (VSM) and BM of ST, a decreased number of ST apical microvilli per unit surface area in the GDM group. These changes related to the reduced VEGFA and VEGFR2 expressions may have adversely affected the transport efficiency of the placental vasculature by the decreased transport of oxygen, nutrients, and waste across the placenta [
36]. To explore the comparable and inchoate changes in the VEGFA and VEGFR2 expression and placental ultrastructure, we excluded those cases with adverse pregnancy outcomes or pathological placental tissuess in this study. Our results suggested that this effect may be a response to the placental hypoxia induced by hyperglycemia, which might have potential affect on the placental and fetal development and growth during pregnancy.