Abstract
Diabetes in pregnancy is associated with adverse pregnancy outcomes including preterm birth. Although the mechanisms leading to these pregnancy complications are still poorly understood, aberrant angiogenesis and endothelial dysfunction play a key role. FKBPL and SIRT-1 are critical regulators of angiogenesis, however, their roles in pregnancies affected by diabetes have not been examined before in detail. Hence, this study aimed to investigate the role of FKBPL and SIRT-1 in pre-gestational (type 1 diabetes mellitus, T1D) and gestational diabetes mellitus (GDM). Placental protein expression of important angiogenesis proteins, FKBPL, SIRT-1, PlGF and VEGF-R1, was determined from pregnant women with GDM or T1D, and in the first trimester trophoblast cells exposed to high glucose (25 mM) and varying oxygen concentrations [21%, 6.5%, 2.5% (ACH-3Ps)]. Endothelial cell function was assessed in high glucose conditions (30 mM) and following FKBPL overexpression. Placental FKBPL protein expression was downregulated in T1D (FKBPL; p<0.05) whereas PlGF/VEGF-R1 were upregulated (p<0.05); correlations adjusted for gestational age were also significant. In the presence of GDM, only SIRT-1 was significantly downregulated (p<0.05) even when adjusted for gestational age (r=-0.92, p=0.001). Both FKBPL and SIRT-1 protein expression was reduced in ACH-3P cells in high glucose conditions associated with 6.5%/2.5% oxygen concentrations compared to experimental normoxia (21%; p<0.05). FKBPL overexpression in endothelial cells (HUVECs) exacerbated reduction in tubule formation compared to empty vector control, in high glucose conditions (junctions; p<0.01, branches; p<0.05). In conclusion, FKBPL and/or SIRT-1 downregulation in response to diabetic pregnancies may have a key role in the development of vascular dysfunction and associated complications affected by impaired placental angiogenesis.
Highlights
Hyperglycaemia is one of the most common pregnancy complications, affecting one in six pregnancies [1]
Overstimulated placental angiogenesis can lead to impairment of the integrity of the vascular system and increased resistance to blood flow leading to hypoxia and the observed syncytial knots; consistent with the observed increased pro-angiogenic and reduced anti-angiogenic factors in these tissues [22]
We demonstrated that expression of the key proteins in placental angiogenesis, FK506-binding protein like (FKBPL), SIRT-1, placental growth factor (PlGF) and vascular endothelial growth factor (VEGF)-R1 [31, 34, 51,52,53], is dysregulated in pregnancies complicated by diabetes with differential molecular changes observed between GDM and T1D
Summary
Hyperglycaemia is one of the most common pregnancy complications, affecting one in six pregnancies [1]. Gestational hypertension and preeclampsia are the leading causes of morbidity and mortality in pregnancy [7], and in the presence of hyperglycaemia, the risk of these conditions is increased up to 4-fold [8]. Elevated fasting blood glucose and HbA1c have been associated with increased risk of preeclampsia in pregnant women with GDM, T1D or T2D [9,10,11]. Hyperglycaemia during pregnancy can lead to several other adverse neonatal complications, including the large for gestational age (LGA) foetus, shoulder dystocia, respiratory distress syndrome and neonatal hypoglycaemia [12]. Hyperglycaemia in pregnancy increases the risk of perinatal death and stillbirth by at least two- to three-fold, in the presence of T1D and T2D compared to healthy pregnant controls [13, 14]. Despite clear epidemiological link between diabetes in pregnancy and both short- and long-term pregnancy complications, the mechanisms of these associations are still poorly understood
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