Diminished nutrient supply stimulates endothelial metabolic rate turnover – impact of the cellular sex on glucose und glutamine metabolism

Endothelial cells must be able to maintain metabolic activity during angiogenesis. At impaired energy levels they have to form new blood vessels to supply the surrounding tissue with oxygen and nutrients. This requires modifications of intracellular metabolism to provide the necessary energy for migration and proliferation. Studies on metabolic adaptions of endothelial cells to diminished energy supply are sparse and investigation of potential sex differences are lacking. We therefore performed a metabolic flux analysis with ¹³ C-glucose or ¹³ C-glutamine labeling for different time points with female and male human umbilical vein endothelial cells (HUVECs) from dizygotic twin pairs. Labeling was performed at basal conditions and after serum starvation for an early and late time point for each labeling. Overall, a much faster label incorporation was found in serum-starved cells. Central carbon metabolites showed a significantly higher label incorporation at both early and late time points for ¹³ C-glucose and ¹³ C-glutamine after serum starvation, independent of the sex of the cells. However, a non-significant but consistent sex-specific pattern was observed. After labeling with ¹³ C-glucose, a higher label incorporation was seen in male cells after serum starvation. In contrast, labeling with ¹³ C-glutamine resulted in a faster label incorporation in female cells, both at basal conditions and after serum starvation. The observed sex differences were coherent throughout the analyzed metabolites. Although not significant and rather small, they could point to subtle sex differences in glucose versus glutamine metabolism in cellular metabolic adaptions to reduced energy supply.