Angiogenesis is an important area of research because the proliferation of blood vessels is crucial to cardiovascular health in the body. As the authors state, angiogenesis relies on the proliferation and migration of endothelial cells which are important to the growth of the vascular network. Although regulatory molecules have been identified, the importance of metabolism has not. Fatty acid oxidation (FAO) has been linked to ATP production but its importance to angiogenesis has not been defined. CPT1 was chosen as the molecule of focus in FAO because it is the rate limiting step of FAO and is likely to have the largest impact when modified. The way the importance CPT1A, the most abundant isoform of CPT1, and CPT1C, a less abundant isoform was detected, was by silencing it. They found that there was a decreased vessel sprout length and number due to decreased endothelial cells (EC). The next step was to study the effects in vivo, using mice that lacked CPT1A which was found to show the same results as the in vitro tests indicating that impairment of angiogenesis was due to EC proliferation defects.
Investigating the mechanism by with FAO regulates EC proliferation was another point of interest for the authors because it helps define its importance to angiogenesis. They highlight several different approaches, each with varying levels of success but provided new information as to the role of FAO in angiogenesis. It was determined that although FAO is involved in ATP production, decreased levels of ATP or energy stress that were causing a lack of sprouting. The authors then suggested a novel role for FAO in EC proliferation given that it is used for de novo synthesis of nucleotides. They found that although impaired ability to synthesize proteins, it did not prevent prevent CPT1A silencing.
The novelty of this article is in the authors’ ability to place the importance of FAO in angiogenesis which had not been done before. In addition, it affected proliferation, not migration, of EC proliferation which is why it can be seen that there is a marked decrease in proliferation, however placement remains somewhat the same. They also discovered a previously unknown role of fatty-acid-derived carbons in de novo deoxyribonucleotide synthesis which provides for carbons for the production of aspartate and glutamate. Although not replaceable for DNA synthesis, they were for protein and RNA synthesis indicated that knock-out CPT1A ECs produced their own rNTPs. These are important discoveries from a human perspective because the proliferation of blood vessels is very important in long-term maintenance of the body in people with cardiovascular problems. It also helps place FAO into a new context and a possible target for drugs.
Although we’re only learning the basics of lipid metabolism, it is important to remember that we only know a fraction of what there is still to discover. There is a lot we still don’t know about the pathways we rely on every day and this is just one tiny piece of a larger puzzle.
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