Fetoplacental vascular endothelial dysfunction as an early phenomenon in the programming of human adult diseases in subjects born from gestational diabetes mellitus or obesity in pregnancy

Abstract

Gestational diabetes mellitus (GDM) and obesity in pregnancy (OP) are pathological conditions associated with placenta vascular dysfunction coursing with metabolic changes at the fetoplacental microvascular and macrovascular endothelium. These alterations are seen as abnormal expression and activity of the cationic amino acid transporters and endothelial nitric oxide synthase isoform, that is, the "endothelial L-arginine/nitric oxide signalling pathway." Several studies suggest that the endogenous nucleoside adenosine along with insulin, and potentially arginases, are factors involved in GDM-, but much less information regards their role in OP-associated placental vascular alterations. There is convincing evidence that GDM and OP prone placental endothelium to an "altered metabolic state" leading to fetal programming evidenced at birth, a phenomenon associated with future development of chronic diseases. In this paper it is suggested that this pathological state could be considered as a metabolic marker that could predict occurrence of diseases in adulthood, such as cardiovascular disease, obesity, diabetes mellitus (including gestational diabetes), and metabolic syndrome.

Figure 1

Comparison of published reports addressing a potential association of human adult diseases in subjects from pregnancies coursing with gestational diabetes mellitus or obesity in pregnancy. Gestational diabetes mellitus (GDM, column of light-blue circles) and obesity in pregnancy (OP, column of orange circles) are pathological conditions in human subjects. Different number of reports (x-axis, Published reports), in this cartoon represented as relative size of corresponding light-blue and orange circles, suggest that GDM and OP are differentially associated with increased incidence of human adult diseases (y-axis, Human adult diseases), such as obesity, type 2 diabetes mellitus (T2DM), insulin resistance, hyperlipidaemia, or hypertension. Data taken from [, , , , , , , –212].

Figure 2

Endothelial L-arginine/NO signalling pathway in gestational diabetes mellitus and obesity in pregnancy. In human endothelial cells L-arginine is taken up via cationic amino acid transporters 1 (hCAT-1) accumulating this amino acid in the intracellular space. L-Arginine is then metabolized by the endothelial nitric oxide synthase (eNOS) into L-citrulline and nitric oxide (NO) as a co-product. Gestational diabetes mellitus is associated with higher expression and activity of hCAT-1 leading to supraphysiological accumulation of L-arginine. This phenomenon results in higher L-arginine metabolism by eNOS due to increased expression and activity of this enzyme leading to overproduction of NO. In endothelial cells from OP there is no information addressing whether this pathological condition alters L-arginine transport and intracellular accumulation, but reduces eNOS expression and activity leading to lower than physiological synthesis of NO.

Figure 3

Adenosine/L-arginine/nitric oxide (ALANO) signalling pathway in gestational diabetes mellitus. Human umbilical vein (macrovasculature) and placental microvascular endothelial cells exhibit increased (solid light-blue arrows) L-arginine transport via the cationic amino acid transporters 1 (hCAT-1) but reduced (segmented light-blue arrows) adenosine uptake via the equilibrative nucleoside transporter 1 (hENT1). The latter phenomenon leads to accumulation (white up arrow) of adenosine in the extracellular space, which then stimulates A_2A adenosine receptors to activate (dotted light-blue arrows) maximal transport capacity of hCAT-1 and maximal metabolic capacity of endothelial nitric oxide synthase (eNOS) leading to supraphysiological levels of nitric oxide (NO) and L-citrulline. The gas NO activates hC/element-binding protein (CBP) homologous protein 10-C/EBPα transcription factor complex (CHOP) leading to repression of SLC29A1 gene expression resulting in reduced hENT1 protein synthesis and abundance at the plasma membrane. On the other hand, NO activates the transcription factor-specific protein 1 (Sp1) and nuclear factor κB (NFκB) leading to increase transcription of SLC7A1 and NOS3 genes, respectively. This phenomenon results in higher abundance of hCAT-1 and eNOS protein increasing L-arginine transport and NO synthesis. From data in [6, 16, 39, 48, 52, 59].

Figure 4

L-Arginine metabolism in hypercholesterolaemia. In human endothelial cells, L-arginine is taken up via cationic amino acid transporter 1 (hCAT-1) which is then metabolized by either the endothelial nitric oxide synthase (eNOS) into L-citrulline and nitric oxide (NO), or via arginases (ARG) into L-ornithine and urea, phenomena conforming a normal endothelial function phenotype. These mechanisms occur in a condition recognized as maternal physiological hypercholesterolaemia (MPH), which has been shown to be associated with early states of fetal vasculature atherosclerosis. However, in a state of maternal supraphysiological hypercholesterolaemia (MSPH) (see text), hCAT-1 and eNOS expression and activity are reduced (white down arrow) leading to reduced (segmented light-blue arrows) L-arginine uptake and NO synthesis, respectively. However, a higher (white up arrow) expression and activity of ARG (most likely arginase 2) leads to increased formation of L-ornithine and urea. The alterations seen in endothelial cells from pregnancies with MSPH result in endothelial dysfunction contributing in a larger proportion to fetal vasculature atherosclerosis compared with MPH. From data in [129, 130, 136, 138].

Figure 5

Potential pathophysiological interaction between the mother, the placenta, and the fetus in fetal atherosclerosis. Maternal factors, including reduced (↓) catalase (CAT) activity, increased (↑) lipid peroxidation, and oxidized low density lipoproteins (oxLDL), associated with increased cholesterol content at the mother circulation, generate a state of maternal supraphysiological hypercholesterolaemia (MSPH). This phenomenon leads to similar alterations in the placenta (reduced CAT, superoxide dismutase (SOD), glutathione-peroxidase (GSH-Px) activity) and the fetus (with reduced CAT and GSH-Px and increased lipid peroxidation and oxLDL). Therefore, atherosclerosis in the fetus is identified. Data taken from [88, 100, 101, 109, 110].

Figure 6

Insulin effect on human umbilical vein ring reactivity. Endothelium-intact human umbilical vein rings were isolated from umbilical veins taken from pregnancies with maternal physiological hypercholesterolaemia (MPH) or maternal supraphysiological hypercholesterolaemia (MSPH). Umbilical vessel ring segments (2–4 mm length) were mounted in a myograph for isometric force measurements with optimal diameter adjusted from maximal active response to 62.5 mM KCl as previously described [28, 107]. Acute response to insulin (3 minutes) was determined in KCl-preconstricted vessels in preparations incubated in Krebs. Values are mean ± SEM (n = 7). *P < 0.05 versus corresponding values in MPH.