Angiogenesis is the process in which blood and lymphatic vessels are formed. Endothelial cells are lined in the interior surface of these vessels. In a recent study conducted by Schoors et al., it was discovered that the proliferation of endothelial cells depend on fatty acid oxidation (FAO) to support the synthesis of dNTPs. They discovered that fatty acids oxidized to acetyl-CoA produces a carbon source in these cells that is needed to produce dNTPs. This discovery has opened the door to ways of preventing disorders caused by uncontrolled angiogenesis such as retinopathy. This particular disease in mice, which causes excessive blood formation that leads to impaired vision, was prevented via the silencing of carnitine palmitoyltransferase 1A (CPT1A) in endothelial cells of mice.
Schoors et al. silenced CPT1A, an enzyme found in mitochondria that is used to import long-chain fatty acids. This prevented the endothelial cells from proliferating, which in turn stopped the harmful growing of excessive blood vessels in the mouse retina. However, after further investigation, the scientists discovered that the amount of energy produced by endothelial cells was not affected when CPT1A was silenced. It also did not inhibit the production of proteins and RNA, which revealed FAO’s role in supporting DNA synthesis. However, it reduced the presence of dNTPs. Once the endothelial cells were replenished with dNTPs, the effects of the silenced CPT1A was reversed. It was discovered that a lack of ATP was not impacting proliferation in endothelial cells that had the silenced enzyme.
This study was a surprising and impactful because FAO providing carbon source for DNA synthesis was not expected. Previous research has shown that cancer cell metabolism relied on the metabolites glutamine and glucose to feed into the acetyl-CoA supply during tumor growth. The study also revealed that endothelial cell migration remained undisturbed while proliferation ceased when CPT1A was silenced. These discoveries show that FAO’s role in endothelial cells are more specialized than glucose metabolism.
Reference: Schoors, S. et al. Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520, 192-197 (2015).