FKBPL and SIRT-1 Are Downregulated by Diabetes in Pregnancy Impacting on Angiogenesis and Endothelial Function

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.

Immunoendocrine Dysregulation during Gestational Diabetes Mellitus: The Central Role of the Placenta

“…Since the placenta is a highly vascularized organ that supplies nutrients, growth factors, oxygen, hormones, and immune mediators to the fetus, all molecules of the angiogenic axis are tightly regulated throughout pregnancy. However, as mentioned before, clinical examination of GDM placentae shows increased villous vascularity often associated with thickened immature villi capillaries [ 20 , 21 , 24 ]. Diverse experimental evidence indicate that hyperglycemia promotes angiogenesis, vasoconstriction, and a higher vessel permeability [ 233 , 234 , 235 , 236 , 237 , 238 ].…”

“…Dr. Lana Mc-Clements found GDM placentae have a decreased expression of the anti-angiogenic protein sirtuin 1 (SIRT-1), which may help to explain the increased vascularized network observed in GDM placentae. Additionally, they cultured a trophoblast cell line (obtained from first trimester/choriocarcinoma) under conditions of hyperglycemia (25 mM) and hypoxia (2.5 and 6.5% O 2 ), and observed a downregulated expression of the anti-angiogenic proteins FK 506 binding protein-like (FKBLP) and SIRT-1 [ 24 ]. These results support the hypothesis that hyperglycemia and lower oxygen tension alter the balance of factors that regulate angiogenesis in the placenta, leading to vascular dysfunction and possibly the development of preeclampsia.…”

“…In addition, it has been hypothesized that this endothelial damage evidenced by increased angiogenesis rate and chorionic villous branching may conduce to increased peripheral vascular resistance. This may explain the higher maternal blood pressure and preeclampsia [ 24 , 239 ], that are highly frequent complications in GDM pregnancies [ 1 , 7 ].…”

“…Reported placental abnormalities in GDM patients include increased placental weight, intimate glycogen deposits, increased number of syncytial knots, villous edema, and larger syncytial area and volume for favoring nutrient uptake [20][21][22][23]. Histopathologic analysis of GDM placentae indicates enhanced angiogenesis and high vasculogenesis rate evidenced by increased villous vascularity often associated with thickened immature villi capillaries and signs of placental hypoperfusion [24,25]. There has also been reported increased fibrinoid necrosis, chorangiosis, and ischemia [25,26].…”

Endothelial Dysfunction in Pregnancy Complications

“…In contrast to those observations, only the expression SIRT-1 gene was significantly downregulated in patients with GDM compared to the controls [176]. Moreover, the high FKBPL expression in HUVECs, evoked by plasmid vector transfection, was associated with a reduction in tubule formation and could be potentially responsible for endothelial dysfunction in vivo [176]. Di Tomo et al reported that HUVECs collected from women with GDM presented alterations in mitochondrial membrane potential and antioxidant response compared with cells obtained in controls.…”