RESUMEN
In chronic kidney disease, hyperphosphatemia is a key pathological factor promoting medial vascular calcification, a common complication associated with cardiovascular events and mortality. This active pathophysiological process involves osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs) via complex intracellular mechanisms that are still incompletely understood. Little is known about the effects of phosphate on the bioenergetic profile of VSMCs during the onset of this process. Therefore, the present study explored the effects of the phosphate donor ß-glycerophosphate on cellular bioenergetics of VSMCs. Mitochondrial and glycolytic functions were determined utilizing extracellular flux analysis in primary human aortic VSMCs following exposure to ß-glycerophosphate. In VSMCs, ß-glycerophosphate increased basal respiration, mitochondrial ATP production as well as proton leak and decreased spare respiratory capacity and coupling efficiency, but did not modify non-mitochondrial or maximal respiration. ß-Glycerophosphate-treated VSMCs had higher ability to increase mitochondrial glutamine and long-chain fatty acid usage as oxidation substrates to meet their energy demand. ß-Glycerophosphate did not modify glycolytic function or basal and glycolytic proton efflux rate. In contrast, ß-glycerophosphate increased non-glycolytic acidification. ß-Glycerophosphate-treated VSMCs had a more oxidative and less glycolytic phenotype, but a reduced ability to respond to stressed conditions via mitochondrial respiration. Moreover, compounds targeting components of mitochondrial respiration modulated ß-glycerophosphate-induced oxidative stress, osteo-/chondrogenic signalling and mineralization of VSMCs. In conclusion, ß-glycerophosphate modifies key parameters of mitochondrial function and cellular bioenergetics in VSMCs that may contribute to the onset of phenotypical transdifferentiation and calcification. These observations advance the understanding of the role of energy metabolism in VSMC physiology and pathophysiology of vascular calcification during hyperphosphatemia. KEY MESSAGES: ß-Glycerophosphate modifies key parameters of mitochondrial respiration in VSMCs. ß-Glycerophosphate induces changes in mitochondrial fuel choice in VSMCs. ß-Glycerophosphate promotes a more oxidative and less glycolytic phenotype of VSMCs. ß-Glycerophosphate triggers mitochondrial-dependent oxidative stress in VSMCs. Bioenergetics impact ß-glycerophosphate-induced VSMC calcification.
