Phosphate and Endothelial Function: How Sensing of Elevated Inorganic Phosphate Concentration Generates Signals in...

Present in all cells, inorganic phosphate (Pi) is involved in regulating a wide range of fundamental cellular processes including energy homeostasis; nucleotide, nucleic acid and phospholipid metabolism; and signalling through protein phosphorylation events. However, at excess concentrations, Pi is known to exert adverse effects on cells, particularly on endothelial cells. This review gives a brief overview of the functional effects of elevated extracellular Pi concentration on mammalian cells and tissues in vitro and in vivo. We then address the cardiovascular effects of elevated extracellular Pi concentration in vitro and in vivo, emphasising that effects have been reported in vivo even within the top end of normal range for plasma [Pi]. Cardiovascular sites of action of Pi are then considered, with a focus on the role of soluble Pi in endothelial dysfunction. The regulation of intracellular Pi concentration by Pi transporter proteins in mammalian cells is described, followed by consideration in detail of how changes in Pi concentration are sensed in mammalian cells and how these trigger functional effects in endothelial cells.