Mitochondrial respiration as a regulator of lymphatic cell fate and therapeutic lymphangiogenesis

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Summary Endothelial cell (EC) metabolism has emerged as an essential driver and regulator of blood and lymphatic vessel development, as well as an alternative approach in anti-angiogenic therapy. It has been shown that metabolism is not only vital to EC function, but also to controlling different steps of the (lymph)-angiogenic process. Lymphatic vessels show remarkable plasticity and heterogeneity, reflecting their functional specialization to control the tissue microenvironment. Our recent findings revealed that by sensing the lymphatic endothelial cell (LEC) differentiation status and microenvironmental metabolic conditions, mitochondrial complex III regulates LEC fate specification and maintenance during embryonic development. Similar to what was shown for blood endothelial cells, most likely in different pathological conditions, mitochondrial respiration is also required for the growth and expansion (lymphangiogenesis) of lymphatics. We argue that mitochondrial respiration sensing and regulation of the metabolic status of LECs is a critical step during developmental and disease-promoted lymphangiogenesis, and we will evaluate this proposal in mouse models of cardiac injury and induced acute and chronic pancreatitis.