A conceptual review of intracellular pH as a regulator of the adenosine–L-arginine–nitric oxide (ALANO) axis in human fetoplacental endothelial dysfunction in gestational diabetes mellitus

This conceptual review provides a synthesising narrative of the interdependent regulation of intracellular pH (pHi), nitric oxide (NO), and adenosine—the pHi–NO–adenosine triad—in fetoplacental endothelial dysfunction associated with gestational diabetes mellitus (GDM). GDM is associated with fetoplacental endothelial dysfunction, involving altered nitric oxide (NO) synthesis, reduced adenosine uptake, and dysregulated intracellular pH (pHi). Human umbilical vein endothelial cells (HUVECs) from GDM pregnancies exhibit increased endothelial NO synthase activity and decreased adenosine transport via human equilibrative nucleoside transporters, processes modulated by NO and pHi. These changes converge in the ALANO (Adenosine/L-Arginine/Nitric Oxide) signalling pathway, which enhances NO synthesis through increased L-arginine uptake. Importantly, similar mechanisms are observed in both macrovascular and microvascular endothelial cells, suggesting widespread placental vascular involvement. Maternal pre-pregnancy body mass index stratification reveals further heterogeneity in these responses. Disruptions in this signalling triad, i.e. NO, adenosine, and pHi, may impair placental perfusion, nutrient delivery, and fetal development, with potential long-term cardiometabolic consequences. Understanding these interrelated mechanisms provides a framework for targeted interventions in GDM, emphasizing the need for personalized approaches in maternal-foetal medicine.