Final Report Summary - ANGIOMET (Angiogenesis-metabolism crosstalk in vascular homeostasis and disease) Historically, angiogenesis has been viewed from the perspective of how endothelial cells coordinate migration and proliferation in response to growth factor activation. However, endothelial cells must also coordinate their metabolism and adapt metabolic fluxes to the rising energy and biomass demands of sprouting vessels. The research project ANGIOMET has provided key insights into the role and regulation of endothelial metabolism during growth and identified novel regulators of the angiogenesis process. For instance, research of the project discovered that the transcription factor MYC is a critical nodal point between growth factor signaling and endothelial metabolism, which prepares endothelial cells for cell growth and division. MYC is highly expressed in sprouting endothelial cells, and its loss causes premature endothelial quiescence and vascular collapse. In collaborative studies, MYC was further identified as a crucial downstream component of FGF signaling, which is required for the regulation of endothelial metabolism during vascular development. Additional studies identified the forkhead transcription factor FOXO1 as an essential regulator of vascular homeostasis that coordinates metabolic and proliferative activities in endothelial cells. This work revealed that endothelial cells are exquisitely sensitive to changes in FOXO1 status as both endothelial-specific deletion and activation are early embryonic lethal in mice. FOXO1 was found to drive endothelial quiescence, in part, by lowering their metabolic rate. The FOXO1-induced reduction in endothelial metabolism was not a secondary stress response but relied on the suppression of MYC. Notably, FOXO1 interfered with MYC signaling at different levels, highlighting the need to restrain the activity of this potent transcriptional regulator. Altogether, these findings led to the model that FOXO function is crucial for keeping the endothelium in a healthy and homeostatic state.
