Is there a role for peroxisomal fatty acid beta-oxidation in vessel sprouting?

Endothelial cells (ECs) line blood vessels to supply nutrients, oxygen and growth factors to tissues. Activation of ECs by growth factors such as VEGF induces vessel sprouting (angiogenesis). The host labs recently postulated that this angiogenic switch requires a metabolic switch, and demonstrated specific roles for glycolysis and mitochondrial fatty acid oxidation (FAO) in vessel sprouting. Like any other cell type, ECs also have peroxisomes, which metabolize very long chain fatty acids (VLCFAs). Multifunctional protein 2 (MFP2) is the key enzyme of peroxisomal ß-oxidation. Surprisingly, nothing is known about the possible role of peroxisomes / peroxisomal FAO in ECs and angiogenesis. Initial data from the host labs indicates that silencing of MFP2 in ECs impairs vessel sprouting. We will use a multidisciplinary approach, combining molecular and cellular biology with conditional mouse genetics, to characterize the importance of MFP2 in vascular sprouging. Moreover, state-of-the-art metabolomics will provide unprecedented insights into the metabolic fate of peroxisomally metabolized VLCFAs, with the ultimate goal of evaluating their physiological relevance in ECs.