HIF-1α is required for disturbed flow-induced metabolic reprogramming in human and porcine vascular endothelium

Hemodynamic forces regulate vascular functions. Disturbed flow (DF) occurs in arterial bifurcations and curvatures, activates endothelial cells (ECs), and results in vascular inflammation and ultimately atherosclerosis. However, how DF alters EC metabolism, and whether resulting metabolic changes induce EC activation, is unknown. Using transcriptomics and bioenergetic analysis, we discovered that DF induces glycolysis and reduces mitochondrial respiratory capacity in human aortic ECs. DF-induced metabolic reprogramming required hypoxia inducible factor-1α (HIF-1α), downstream of NAD(P)H oxidase-4 (NOX4)-derived reactive oxygen species (ROS). HIF-1α increased glycolytic enzymes and pyruvate dehydrogenase kinase-1 (PDK-1), which reduces mitochondrial respiratory capacity. Swine aortic arch endothelia exhibited elevated ROS, NOX4, HIF-1α, and glycolytic enzyme and PDK1 expression, suggesting that DF leads to metabolic reprogramming in vivo. Inhibition of glycolysis reduced inflammation suggesting a causal relationship between flow-induced metabolic changes and EC activation. These findings highlight a previously uncharacterized role for flow-induced metabolic reprogramming and inflammation in ECs. DOI: http://dx.doi.org/10.7554/eLife.25217.001
eLife digest Atherosclerosis is the build-up of fatty material inside the blood vessels, and is one of the leading causes of heart disease and stroke. The blood vessels affected are typically inflamed for many years before the condition develops, and the condition often occurs at sites where blood vessels branch or turn. The cells that line the inside of the blood vessels are known as endothelial cells. Flowing blood exerts a force upon the endothelial cells, named “shear force”, which is similar to how wind bends plants. When the blood flows in one direction, the shear forces are high, the endothelial cells are tightly held together, and the vessels are less likely to become inflamed. However, the flow of blood is disturbed around turns or branch points. This means thatthe shear forces are lower and that the gaps between the endothelial cells are bigger. Low shear forces also mean that the endothelial cells release chemical signals that promote the inflammation and ultimately leads to atherosclerosis. Though low shear forces play an important role in “activating” endothelial cells to promote inflammation, it was not clear how this happens. Wu et al. now show that when shear forces inside blood vessels are low, endothelial cells promote inflammation by modifying their own metabolism. The experiments involved applying either high or low shear forces to endothelial cells that had originally been collected from a major blood vessel of human donors, and then grown in the laboratory. Wu et al. then analyzed the gene activity of these endothelial cells and discovered that low shear forces activate a selected pool of genes. The activated genes are mainly responsible for two cellular processes: glycolysis and the response to hypoxia. Glycolysis is a process that releases energy by breaking down the sugar glucose, while hypoxia refers to the situation when cells do not receive enough oxygen. Further molecular analyses revealed that low shear forces stabilize a particular protein involved in the response to hypoxia, named HIF-1α, and that this protein is responsible for stimulating glycolysis. Finally, Wu et al. showed that increasing glycolysis in endothelial cells was enough to cause the blood vessels to become inflamed. Going forward, a better understanding of how low shear forces modify the metabolism of endothelial cells in blood vessels and consequently promote inflammation will help scientists to tackle new questions about how atherosclerosis begins and develops. In the longer-term, these findings might also lead to the development of new treatments to atherosclerosis and similar diseases. DOI: http://dx.doi.org/10.7554/eLife.25217.002