Abstract
Placentas from gestational diabetes mellitus (GDM) are often hypervascularized; however, participation of vascular endothelial growth factor (VEGF) and its receptors in this placental adaptation is unclear. We aimed to test whether changes in phosphorylation of tyrosine 951 or tyrosine 1175 (pY951 or pY1175) of the vascular endothelial growth factor receptor 2 (KDR) are associated with the proangiogenic state observed in placentas from GDM. We obtained placental samples from women with normal pregnancies (n = 24) or GDM (n = 18). We measured the relative expression of markers for endothelial cell number (CD31, CD34), VEGF, vascular endothelial growth factor receptor 1 (Flt-1), KDR, pY951 and pY1175 of KDR in placental homogenate. Immunohistochemistry of placental blood vessels were performed using CD34. Proliferation and migration of human umbilical vein endothelial cells (HUVEC) obtained from normal pregnancy and GDM were determined in absence or presence of conditioned medium (CM) harvested from GDM or normoglycemic HUVEC cultures. GDM was associated with more CD31 and CD34 protein compared to normal pregnancy. High number, but reduced area of placental blood vessels was found in GDM. Reduced Flt-1 levels (mRNA and protein) are associated with reduced KDR mRNA, but higher KDR protein levels in placentas from GDM. No significant changes in Y951-or Y1175-phosphorylation of KDR in placentas from GDM were found. GDM did not alter proliferation of HUVECs, but enhanced migration. Conditioned medium harvested from GDM HUVEC cultures enhanced KDR protein amount, tube formation capacity and cell migration in HUVEC isolated from normoglycemic pregnancies. The data indicate that GDM is associated with reduced expression of Flt-1 but high pro-migratory activation of KDR reflecting a proangiogenic state in GDM.
Highlights
Gestational diabetes mellitus (GDM) affects at least 1 in 10 pregnant woman worldwide [1, 2] and accounts for a range of adverse perinatal outcomes including, among others, excessive fetal fat accretion (‘macrosomia’), fetal hypoglycemia, requirement of neonatal intensive care and neonatal mortality [2,3,4,5]
The results of this study suggest that placentas from GDM pregnancies are in a proangiogenic state, since they have more endothelial cells i.e., elevated endothelial cell markers and placental blood vessels per chorionic villi, as well as higher level of total vascular endothelial growth factor receptor 2 (KDR) than placentas from normal controls
We have to acknowledge that CD31 and CD34 are present on hematopoietic progenitor cells, which may or may not contribute to hypervascularization in GDM [26]
Summary
Gestational diabetes mellitus (GDM) affects at least 1 in 10 pregnant woman worldwide [1, 2] and accounts for a range of adverse perinatal outcomes including, among others, excessive fetal fat accretion (‘macrosomia’), fetal hypoglycemia, requirement of neonatal intensive care and neonatal mortality [2,3,4,5]. GDM causes short-term complications in the newborn, but is associated with an elevated risk for chronic conditions such as cardiovascular disease, obesity and diabetes [6, 7]. The placenta is an essential organ for fetal growth and development. Compared to normal pregnancies, placentas from GDM exhibit enhanced vascularization [9, 10]. This may appear counterintuitive in a situation of maternal nutritional oversupply, but reflects the increased oxygen demand of the fetus, because of the insulin-stimulated enhanced fetal aerobic metabolism [10]. The mechanisms underlying enhanced angiogenesis have not been fully elucidated
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