EC METABOLISM

Understanding the metabolism of endothelial cells underlying physiological and pathological angiogenesis

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 Obiettivo del progetto (Objective)

'Angiogenesis is the process whereby new blood vessels are formed. Physiological angiogenesis occurs in a variety of settings, including embryogenesis, wound healing and inflammation. Pathological angiogenesis may occur in such settings as tumor and atherosclerotic neovascularization. Endothelial cells exhibit remarkable plasticity and can rapidly transition to migratory and proliferative phenotypes. This phenotypic transformation not only changes cellular physiology, but also cellular metabolic requirements, and thus cellular metabolism.

The proposed research focuses on understanding the metabolism of endothelial cells underlying physiological and pathological angiogenesis. By specifically targeting the metabolic energy supply of tumor microvasculature, we hope to be able to limit tumor growth and metastasis while minimizing side effects to normal cells. Conversely, we believe that this knowledge will allow us to promote physiological angiogenesis in such settings as wound healing and myocardial infarction.

There is a great deal of heterogeneity within endothelial cells and their biological functions, as they must be specialized to deal with their specific environments and tissue interactions. Arterial endothelial cells are generally quiescent and are exposed to high oxygen and glucose concentrations, as they line the primary conduit for nutrient delivery in the circulatory system. On the other hand, venous endothelial cells are often in deoxygenated environments and can function in sprouting and transport. Finally, lymphatic endothelial cells are often in anoxic environments (lacking oxygen) and have been characterized to participate in lipid uptake, inflammation and metastasis.

Thus, we hypothesize that there are fundamental differences in the basal metabolism of endothelial cells of arterial, venous and lymphatic origin. In this proposal, we aim to address the unknown but important questions of whether cellular metabolism defines the fate endothelial cells.'

Introduzione (Teaser)

Our bodies are capable of forming new blood vessels, a process known as angiogenesis. Studying the molecular triggers of this phenomenon could lead to the design of novel therapeutic interventions.

Descrizione progetto (Article)

The growth of new blood vessels occurs during embryogenesis, wound healing and inflammation but also under pathological situations such as cancer or atherosclerosis.

Scientists on the EU-funded EC METABOLISM (Understanding the metabolism of endothelial cells underlying physiological and pathological angiogenesis) study aimed to understand the metabolic alterations in endothelial cells undergoing physiological or pathological angiogenesis. For this purpose, they studied the basal metabolism of endothelial cells of arterial, venous and lymphatic origin.

Metabolism is the breakdown of nutrients to produce energy and building blocks necessary for cellular function and growth. Endothelial cells line all the vessels in the body, which provide nutrients and oxygen to the tissues.

EC METABOLISM scientists found that lymphatic endothelial cells have higher fatty acid oxidation flux compared to venous or arterial cells. Considering the higher lipid content of lymph and the role of the lymphatics in regulating reverse cholesterol transport in atherosclerosis, this finding is of high medical relevance.

To further elucidate the role of fatty acid oxidation in lymphatic vessel formation, the consortium used transgenic zebrafish and a mouse model of lymphatic development. They discovered that the transcription factor that drives lymphatic development and lymphatic endothelial cell differentiation is also responsible for elevated fatty acid oxidation. Mechanistic insight into the process indicated that fatty acid metabolism regulates epigenetic modifications and promotes the transcription of lymphatic genes.

The EC METABOLISM observations provided concrete evidence on the link of endothelial cell phenotype, metabolism and environment. Most importantly they paved the way for determining the therapeutic potential of inhibition of fatty acid oxidation in pathological lymphangiogenesis.