Gestational Diabetes Mellitus and the Role of Adenosine in the Human Placental Endothelium and Central Nervous System

Abstract

Diabetes mellitus is a syndrome that alters macro and microvascular reactivity as a result of endothelial dysfunction. This phenomenon occurs in vascular beds from different regions in the adult human body, as well as the developing fetus including the placenta and the brain vasculature. The human placenta is highly vascularized lacking of innervation, so that blood flux is governed by locally released vasoactive moleculles, including the endogenous nucleoside adenosine and the gas nitric oxide (NO). Altered adenosine uptake by the endothelium leads to increased synthesis of NO resulting in repression of equilibrative nucleoside membrane transporters isoforms 1 (hENT1) and 2 (hENT2). The latter result in higher extracellular adenosine and activation of adenosine receptors (ARs) sustaining tonic activation of NO synthesis in gestational diabetes mellitus (GDM). Similar alterations are apparent in the fetus brain. Because GDM associates with serious alterations in the CNS functions leading to abnormal higher cognitive functions, among others complications, it is proposed that altered adenosine metabolism, uptake and dynamics of ARs activation in the brain is a factor leading to these pathologies. We here summarize the findings available in the literature regarding these mechanisms in the human fetus brain with reference to that in the feto-placental circulation. We emphasize the possibility that adenosine plays a key role in the functional link established by astrocytes connecting neurons and the brain vasculature. This phenomenon is altered in the brain and the feto-placental vasculature, which could be crucial for understanding GDM deleterous effects in fetal growth and development, as well as CNS abnormal function in adulthood.