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Peter Carmeliet

Laboratory of Angiogenesis and Vascular Metabolism

The research group of Peter Carmeliet focuses since 18 years on a central theme, i.e. unraveling the molecular basis of Angiogenesis (i.e. the formation of blood vessels) and translating these genetic insights in therapeutic concepts and, if possible, novel treatments.

Latest findings indicate that efficacy of current anti-angiogenic therapy (targeting VEGF) in cancer is limited by intrinsic refractoriness and acquired drug resistance. There is thus a large unmet medical need to improve clinical anti-angiogenic therapy. To remedy this problem, Peter Carmeliet’s team uses a fundamentally distinct approach and pioneered the study of endothelial cell (EC) metabolism during vessel sprouting, hypothesizing that targeting this “engine” of ECs would paralyze blood vessel growth, regardless of the available pro-angiogenic signals.

Recent studies from the group showed that during the angiogenic switch, when quiescent endothelial cells change to an active migratory or proliferative phenotype, the cells reprogram their metabolism to meet the changed demand of energy and biomass. Moreover, interfering with specific metabolic pathways stimulated or inhibited angiogenesis in vitro and in physiological and pathological models in vivo. Together, the data demonstrated that metabolism co-determines endothelial cell responses, and can even overrule genetic regulatory signals, a concept that was previously not recognized. These findings offer novel opportunities for pro- and anti-angiogenic therapies of pathologies in which aberrant blood vessel formation or function is an important determinant.

Over the years, we have performed “reverse” profiling of endothelial cell metabolism, i.e. we select a metabolic target and, by genetically deleting this target from ECs, we study its role in angiogenesis in vitro and in preclinical animal models in vivo. This “reverse” approach provided ground-breaking insights in the role of metabolic pathways in ECs. By using this approach, we showed that ECs are glycolysis-addicted (Cell, 2013) and that partial and transient inhibition of glycolysis (by blockade of the glycolytic activator PFKFB3) sufficed to inhibit pathological angiogenesis (ocular disease, inflammatory disease) without causing systemic effects (Cell Metabolism and Cell Cycle, 2014). In addition, we discovered that ECs use fatty acid oxidation (FAO) by fuelling de novo deoxyribonucleotide synthesis for DNA replication (Nature, 2015). This novel discovery about the role of FAO provides fundamental new insights and offers new therapeutic opportunities. Furthermore, pharmacological blockade of FAO inhibited pathological angiogenesis thereby hinting at the potential translational value of these findings as novel therapeutic strategy for the current limited cancer therapies. Moreover, a follow-up study in lymph vessels shows that differentiation of venous to lymphatic ECs relies on the use of fatty acid-derived acetyl-CoA as a signaling metabolite for epigenetic reprogramming of the differentiation switch, a paradigm-shifting discovery when considering that nothing is known about the metabolism of lymphatic ECs and that a role of metabolism in regulating lymphatic EC differentiation was never considered previously. To study the role of key metabolic enzymes in endothelial cell biology and angiogenesis in vivo, over 35 conditional knock-out mouse strains are available for phenotypic analysis.

To address the next question as to which metabolic pathways are derailed in vascular disease, we are performing a novel research line of “Forward” profiling of EC metabolism by using a combination of state-of-the-art targeted and untargeted approaches. This will be the next step to translate our EC metabolism studies to the clinic, more in particular to study EC metabolism in (human) disorders. We hypothesize that maladaptations of EC metabolism promote excess angiogenesis (e.g. in cancer) or dysfunctional endothelium (e.g. in diabetes and neurological/ neurodegenerative pathologies). While the “reverse” approach is hypothesis-driven, the “forward” strategy is exploratory, hypothesis-generating, with a high potential of identifying new targets. It creates new horizons for a better understanding of vascular disorders and discovering novel roles of metabolism in ECs.

Profiling of metabolic changes in ECs in health and disease occurs through comparison of isolated endothelial cells from patient samples and healthy controls, and identification, via a multidisciplinary set of state-of-the-art profiling methods, which metabolic pathways are abnormal and functionally relevant for the particular disease. Metabolic profiling is done using radiolabeled substrate-based assays, GC/LC-MS for metabolite level determination and 13C-labeled tracers for metabolic fate analysis (collaboration with B. Ghesquiere, VIB). Validation of the findings is performed using genetic or pharmacological inhibition of metabolic pathways in in vitro models and in angiogenesis models in zebrafish and mouse. Finally, for evaluation of preclinical therapeutic intervention, mouse models of pathological angiogenesis are used (tumor models, models of ocular neovascularization, diabetes, neurodegeneration, etc.).

 

 

Events

Karen Vousden, Paolo Sassone-Corsi, Christian Frezza, Nika Danial
12/09/2017 - 09:00