Endothelial cells are a particular cell type that contribute to angiogenesis (the formation of blood vessels) via proliferation and migration. It was believed that cells used sugars as the main `carbon source for metabolism in order to generate the necessary energy and biomass for proliferation, however in the article Fatty acid carbon is essential for dNTP synthesis in endothelial cells, Schoors et al. report findings of a novel source for carbons.
While fatty acid oxidation (FAO) has previously been related to ATP production and reactive oxygen species in response to cellular stress, the role of FAO in angiogenesis was unknown. By targeting carnitine palmitoyltransferase 1 (CPT1), the rate limiting step in FAO, Schoors et al. were able to identify FAO as a carbon source for endothelial cell proliferation.
To study CPT1, Schoors et al. created knockdown cells that had inactivated CPT1 and saw a significantly lower proliferation of cells. By studying ATP levels and ATP/ADP ratios, they were able to identify that the absence of CPT1 did not impair proliferation by lowering energy production. Additionally, they found that reactive oxygen species levels did not increase significantly, indicating that the effects were also not caused by toxic reactive oxygen species levels.
Using isotopic carbon labeling, Schoors et al. found that the carbons from FAO were incorporated in the citric acid cycle, which was particularly surprising considering that prior studies indicated glucose and glutamine as the source of the citric acid cycle. Schoors et al. explored the use of the citric acid cycle intermediates in various biomass productions and found that the inhibition of CPT1 impacted nucleotide synthesis, but not that of RNA or proteins. This established their findings that FAO was necessary for angiogenesis in endothelial cells.
Their work is particularly impactful as it proposes a completely new pathway for nucleotide synthesis. Furthermore, it shows that FAO is not only a contributing pathway, but an essential pathway in nucleotide synthesis. This pathway seems to only be necessary in the proliferation of endothelial cells and fibroblasts, but not other cell types or migration. This specialized role makes FAO a promising target for treatment, especially considering that the targeting of FAO does not appear to impact protein or RNA synthesis. Because of the role of endothelial cells in angiogenesis, this becomes particularly useful when treating diseased related to excessive angiogenesis as well as cancer. Schoors et al. demonstrate not only the role of FAO in endothelial cell proliferation, but also a targeted inhibition method with which to pursue treatment in further studies.
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