The Impact of Insulin Treatment on the Expression of Vascular Endothelial Cadherin and Beta-Catenin in Human Fetoplacental Vessels

Abstract

Vascular endothelial cadherin and β-catenin play a key role in establishment and maintenance of the endothelial monolayer integrity, regulation of vascular barrier function, and initiation of angiogenesis. The cadherin-catenin complex has been shown to be reduced in type 1 diabetic placenta, but the exact relationship between histopathologic findings and clinical data is not known. Immunohistochemistry of placental tissue from type 1, type 2, and gestational diabetes showed that diabetes per se might be compatible with normal levels of vascular endothelial (VE)-cadherin and β-catenin in fetoplacental vessels as long as the patient has not been treated with insulin. Immunoreactivity of VE-cadherin did correlate poorly with maternal glycemic control, as was investigated in this study, by birth weight, body mass index, and hemoglobin A1c (HbA1c). There was no correlation found between the immunoreactivity of β-catenin and birth weight, body mass index, or HbA1c. However our data did show a strong correlation between immunoreactivity and whether or not the patient had been treated with insulin. Patients diagnosed with gestational diabetes who had not been treated with insulin had similar levels of VE-cadherin and β-catenin to the control group, thus indicating that diabetes per se must not necessarily lead to a reduction. Our study suggests that therapeutic intervention using insulin in pregnancies complicated by diabetes might have potentially harmful effects on placental morphology. Future studies should further investigate these findings.

Review: Placental transport and metabolism of energy substrates in maternal obesity and diabetes

“…Treatment with insulin in women with pre-existing diabetes and GDM positively correlates 242 with placental expression of vascular endothelial (VE)-cadherin and β-catenin in 243 fetoplacental vessels [75], supporting the notion that maternal insulin affects placental 244 function directly. 245…”

Low molecular weight heparin (nadroparin) improves placental permeability in rats with gestational diabetes mellitus via reduction of tight junction factors

“…Previous studies have suggested that placental dysfunction in patients with GdM is caused by hyperglycemia (6,7). in addition, other studies have identified that insulin therapy does not improve fetal or newborn metabolic outcomes (8), and that it can cause alterations in the placenta (9), indicating factors other than glucose may be involved in the pathophysiology of GdM. in a number of studies, advanced glycation end products (AGEs) have been identified to be present in higher levels in women suffering from GdM (10,11) and these products are associated with poor fetal outcomes (12).…”

Renal endothelial protein C receptor expression and shedding during diabetic nephropathy

“…The reduced shedding of EPCR that occurred as a result of inhibition of ADAM‐17 was accompanied by increased mRNA expression of endothelium‐specific VE‐cadherin, an important intercellular junction component that controls endothelial integrity. At the same time, inhibition of ADAM‐17 resulted in decreased mRNA levels of TGF‐β, a marker of endothelial–mesenchymal transition that is critically implicated in the pathogenesis of DN . Silencing of ADAM‐17 by siRNA reproduced the effects of ADAM‐17 blockade on endothelial phenotype.…”