RESUMO
The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis.
Assuntos
Carbono/metabolismo , Células Endoteliais/metabolismo , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Nucleotídeos/biossíntese , Ácido Acético/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Vasos Sanguíneos/citologia , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Carnitina O-Palmitoiltransferase/deficiência , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclo do Ácido Cítrico , DNA/biossíntese , Modelos Animais de Doenças , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/enzimologia , Inativação Gênica , Glucose/metabolismo , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Camundongos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Nucleotídeos/química , Nucleotídeos/farmacologia , Oxirredução/efeitos dos fármacos , Retinopatia da Prematuridade/tratamento farmacológico , Retinopatia da Prematuridade/metabolismo , Retinopatia da Prematuridade/patologiaRESUMO
PURPOSE OF REVIEW: Endothelial cells line the blood vessel lumen and are critical for blood flow homeostasis. Excessive and deregulated vessel overgrowth is a hallmark of pathological (tumor) angiogenesis. The purpose of this review is to describe the metabolic features of endothelial cells, in comparison with those of the cancer cells, and to discuss novel antiangiogenesis approaches based on targeting endothelial cell metabolism. RECENT FINDINGS: To form new blood vessels, endothelial cells switch from quiescence to a highly active state, characterized by migration and proliferation of endothelial cells. To date, growth factors, cytokines, and other molecules have been demonstrated to regulate vessel sprouting. However, recent evidence indicates that endothelial cell metabolism also importantly regulates angiogenesis. Whereas cancer cell metabolism has been studied extensively, endothelial cell metabolism is still in its infancy. SUMMARY: We will discuss metabolic pathways that regulate vessel sprouting, and highlight the commonalities with cancer cells for as much as studied. We will also consider new opportunities for the development of alternative antiangiogenic therapies by targeting endothelial cell metabolism.