Role of Insulin and Adenosine in the Human Placenta Microvascular and Macrovascular Endothelial Cell Dysfunction in Gestational Diabetes Mellitus

Abstract

Microvascular and macrovascular endothelial function maintains vascular reactivity. Several diseases alter endothelial function, including hypertension, obesity, and diabetes mellitus. In addition, micro- and macrovascular endothelial dysfunction is documented in GDM with serious consequences for the growing fetus. Increased l-arginine uptake via hCAT-1 and NO synthesis by eNOS is associated with GDM. These alterations are paralleled by activation of purinergic receptors and increased umbilical vein, but not arteries blood adenosine accumulation. GDM associates with NO-reduced adenosine uptake in placental endothelium, suggested to maintain and/or facilitate insulin vasodilation likely increasing hCAT-1 and eNOS expression and activity. It is proposed that increased umbilical vein blood adenosine concentration in GDM reflects a defective metabolic state of human placenta. In addition, insulin recovers GDM-alterations in hCAT-1 and eNOS in human micro- and macrovascular endothelium, and its biological actions depend on preferential activation of insulin receptors A and B restoring a normal-like from a GDM-like phenotype. We summarized existing evidence for a potential role of insulin/adenosine/micro- and macrovascular endothelial dysfunction in GDM. These mechanisms could be crucial for a better management of the mother, fetus and newborn in GDM pregnancies.

Human supraphysiological gestational weight gain and fetoplacental vascular dysfunction

“…15,19,20 Reduced expression and activity of hENT1 is known to lead to extracellular accumulation of adenosine in HUVECs primary cultures, 19 and inhibition of hENT1 increases the dilation of human umbilical vein rings. 18 Our results show that v i and overall adenosine transport was reduced in HUVECs from spGWG, suggesting altered membrane transport mechanisms mediating the removal of extracellular adenosine.…”

Physiological mechanisms of vascular response induced by shear stress and effect of exercise in systemic and placental circulation

“…In HUVECs from GDM or incubated with high concentration of D -glucose, there is high synthesis of NO (Sobrevia et al, 1995), related with high expression of the main L -arginine transporter: hCAT-1 (González et al, 2004, 2011; Guzmán-Gutiérrez et al, 2014). L -Arginine is the substrate for NO synthesis by eNOS (Alderton et al, 2003) and the transport of L -arginine is essential for NO synthesis in the endothelium (Shin et al, 2011).…”

Role of Insulin in Placental Transport of Nutrients in Gestational Diabetes Mellitus

“…Recent studies have shown the altered expression of IRs in the fetoplacental endothelium of GDM women, leading to abnormal fetal endothelium function [24], even when GDM is treated with diet containing normal levels of glucose. Nevertheless, insulin treatment was seen to restore IR expression in these patients leading to normal endothelial function and a normal newborn [25].…”