Gestational diabesity and foetoplacental vascular dysfunction

Abstract

Gestational diabetes mellitus (GDM) shows a deficiency in the metabolism of Dglucose and other nutrients, thereby negatively affecting the foetoplacental vascular endothelium. Maternal hyperglycaemia and hyperinsulinemia play an important role in the aetiology of GDM. A combination of these and other factors predisposes women to developing GDM with pre-pregnancy normal weight, viz. classic GDM. However, women with GDM and prepregnancy obesity (gestational diabesity, GDty) or overweight (GDMow) show a different metabolic status than women with classic GDM. GDty and GDMow are associated with altered l-arginine/nitric oxide and insulin/adenosine axis signalling in the human foetoplacental microvascular and macrovascular endothelium. These alterations differ from those observed in classic GDM. Here, we have reviewed the consequences of GDty and GDMow in the modulation of foetoplacental endothelial cell function, highlighting studies describing the modulation of intracellular pH homeostasis and the potential implications of NO generation and adenosine signalling in GDty-associated foetal vascular insulin resistance. Moreover, with an increase in the rate of obesity in women of childbearing 2 of 15 | CORNEJO Et al.

Placental Endocrine Activity: Adaptation and Disruption of Maternal Glucose Metabolism in Pregnancy and the Influence of Fetal Sex

“…Hyperglycemia during pregnancy is consistently associated with adverse maternal and neonatal outcomes [ 18 ], and markedly contributes to health risks after birth in both mothers and babies. This leads to a further amplification of the pandemic of non-communicable diseases [ 15 , 19 ].…”

The birth of cardiac disease: Mechanisms linking gestational diabetes mellitus and early onset of cardiovascular disease in offspring

“…The compromised NO metabolism pathway found in the umbilical vein cord from human pregnancies complicated by GDM (Contreras‐Duarte et al, 2021; L. Sobrevia et al, 1998; Vásquez et al, 2004) has been proposed to lead to increased levels of the NO precursor L‐Arg transport, increased protein levels and activity of the cationic amino acid transporter (CAT‐1), and increased NO synthesis (Contreras‐Duarte et al, 2021; L. Sobrevia et al, 1998; Vásquez et al, 2004). Overstimulation of NO metabolism in the fetoplacental unit in GDM‐characterized pregnancies is associated with vascular dysfunction (Cabalín et al, 2019; Cornejo et al, 2021; Jensen et al, 2016; Valero et al, 2021), through a possible rise in ONOO − levels (Morton et al, 2016). This free radical is involved in lipid peroxidation, causing cell damage through cell membrane disruption (Cornejo et al, 2021; Morton et al, 2016).…”

“…Overstimulation of NO metabolism in the fetoplacental unit in GDM‐characterized pregnancies is associated with vascular dysfunction (Cabalín et al, 2019; Cornejo et al, 2021; Jensen et al, 2016; Valero et al, 2021), through a possible rise in ONOO − levels (Morton et al, 2016). This free radical is involved in lipid peroxidation, causing cell damage through cell membrane disruption (Cornejo et al, 2021; Morton et al, 2016). The vascular fetoplacental dysfunction has been reported as being partly caused by the GDM‐induced inflammation, as pointed out by increased levels of monocytes in GDM‐maternal blood (Angelo et al, 2018), and increased levels of pro‐inflammatory cytokines, such as TNF‐α, and IL‐6 in GDM‐maternal serum levels (Cabalín et al, 2019).…”

“…Indeed, human placenta resultant from GDM pregnancies present decreased activity of the oxidative phosphorylation system (OXPHOS; Muralimanoharan et al, 2016), decreased mitochondrial respiration, and decreased ATP production (Fisher et al, 2021), along with increased fusion events (as evidenced by predominantly elongated mitochondria and altered expression of proteins from the mitochondrial fusion and fission machinery, such as optic atrophy protein 1 [OPA1] and active dynamin‐related protein 1 [DRP1]), possibly as a compensatory mechanism (Abbade et al, 2020). GDM‐associated alterations in placental morphology, metabolism, and mitochondrial function lead to an impairment in placental development, thus affecting placental buffering ability, placental excretome, and the transport of nutrients required for suitable fetal cardiovascular system development (Cornejo et al, 2021; Fisher et al, 2021; Gauster et al, 2012).…”

Exposome and foetoplacental vascular dysfunction in gestational diabetes mellitus

“…Various disruptors present in the environment can cause abnormal foetus growth and development. The harmful effect of these disruptors associates with molecular signatures imprinted in the newborn and the mother, thereby becoming the base of future diseases in adulthood and future pregnancies (Cornejo et al, 2021;Hill, 2021;Kupper and Huppertz, 2021;Lucock, 2021).…”