Endothelial metabolism during angiogenesis
Angiogenesis plays a critical role during development and in many pathological conditions. In 2013, Katrien (during her postdoc in the Carmeliet lab, VIB and KU Leuven, Belgium) showed a crucial role for metabolism in the regulation of angiogenesis and found that endothelial cells (ECs) predominantly use anaerobic glycolysis for ATP production. Moreover, during angiogenesis they upregulate glycolysis even further to fuel migration and proliferation. In vitro and in vivo sprouting assays revealed that suppression of glycolysis via inhibition of the glycolytic regulator PFKFB3 in ECs impaired developmental and pathological angiogenesis (De Bock et al., Cell 2013 – Schoors*, De Bock et al, Cell Metabolism 2014). These observations underscored the critical role of endothelial metabolic rewiring during angiogenesis and conceptually showed that metabolism can control EC function.
Since 2015, the Laboratory of Exercise and Health has continued to study how ECs metabolism drives EC functions. We use several developmental and pathological models for angiogenesis, but focus on understanding the metabolic and molecular drivers of exercise-induced physiological angiogenesis (for review see Gorski and De Bock, Vascular Biology 2019) and ischemia-induced angiogenesis as a preclinical model of peripheral artery disease. To do so, we combine the -omics approaches with in vivo, ex vivo, and in silico experimental tools (where necessary in fruitful collaborations).
We found that endothelial cells depend on GLUT1 for glucose import to fuel glycolysis (Veys et al, Circulation research 2020), but do not use GLUT1 to transport glucose into skeletal muscle (Zhang et al, Cell Metabolism 2024).
Our studies (Fan et al, Cell Metabolism 2021) have also revealed remarkable metabolic angiodiversity within muscle capillary endothelial cells. Using single cell sequencing, we identified two capillary subpopulations characterized by the expression of ATF3/4. We subsequently embarked on a series of in vitro and in vivo knock-down approaches combined with functional, genetic and metabolic profiling to show that ATF3/4+ ECs are more angiogenic when compared to ATF3/4 ECs. Mechanistically, we showed that ATF3/4 in muscle ECs control genes involved in amino acid uptake and metabolism and metabolically prime ECs for angiogenesis. Consequently, deleting Atf4 in ECs impaired exercise-induced angiogenesis. Following up on these observations, we recently confirmed the presence of ATF3/4+ ECs in human muscle and showed that under pathological conditions like peripheral artery disease, muscle ECs lose their transcriptional characteristics (Turiel et al., 2025, Nature Cardiovascular Research).
