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
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 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].
