Hallmarks of Endothelial Cell Metabolism in Health and Disease

Abstract

In 2009, it was postulated that endothelial cells (ECs) would only be able to execute the orders of growth factors if these cells would accordingly adapt their metabolism. Ten years later, it has become clear that ECs, often differently from other cell types, rely on distinct metabolic pathways to survive and form new blood vessels; that manipulation of EC metabolic pathways alone (even without changing angiogenic signaling) suffices to alter vessel sprouting; and that perturbations of these metabolic pathways can underlie excess formation of new blood vessels (angiogenesis) in cancer and ocular diseases. Initial proof of evidence has been provided that targeting (normalizing) these metabolic perturbations in diseased ECs and delivery of metabolites deserve increasing attention as novel therapeutic approaches for inhibiting or stimulating vessel growth in multiple disorders. Endothelial Metabolic Pathways Securing BioenergeticsCellular metabolism serves at least three main purposes, i.e., energy production, biomass synthesis, and redox homeostasis, in

Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1

“…Once activated by pro-angiogenic factors, endothelial cells (ECs) sprout to extend the vasculature and to supply the growing tumors with oxygen and nutrients [ 1 ]. While angiogenesis is an enticing target, therapies based on vascular endothelial growth factor (VEGF) blockade have shown limited results due to upregulation of alternative proangiogenic growth factors [ 1 , 2 ].…”

“…Once activated by pro-angiogenic factors, endothelial cells (ECs) sprout to extend the vasculature and to supply the growing tumors with oxygen and nutrients [ 1 ]. While angiogenesis is an enticing target, therapies based on vascular endothelial growth factor (VEGF) blockade have shown limited results due to upregulation of alternative proangiogenic growth factors [ 1 , 2 ]. In contrast, targeting EC metabolism should impair angiogenesis, regardless of how many angiogenic signals are present [ 1 ] The dependency of proliferating ECs on glucose but also glutamine and fatty acids for energy and biomass production opens new opportunities for anti-angiogenic therapy in cancer [ 3 , 4 , 5 ].…”

Ophiopogonin D promotes bone regeneration by stimulating CD31hiEMCNhi vessel formation

“…a specific microenvironment that decides the fate of progenitor cells. [15][16][17][18][19][20] Therefore, it is important to investigate the effects of vessels on tissue regeneration. CD31 hi EMCN hi vessels (CD31, also known as PECAM1 [platelet and endothelial cell adhesion molecule 1]; EMCN, endomucin), which are strongly positive for CD31 and endomucin, are specific vessels in the skeletal system that couple angiogenesis and osteogenesis.…”

Metabolic pathway alterations in microvascular endothelial cells in response to hypoxia

“…Our findings are of broad relevance to the vasculature in the context of other pathophysiologies, including cardiovascular disorders, ocular diseases, diabetes, and brain aneurysms, as well as to normal physiologies exposed to hypoxia (32,33,36,67). Many of these disease states exhibit increased ROS similar to what is observed in hypoxia.…”

“…Exploring reprogramming of metabolic enzymes and pathways in specific tumor types has identified unique metabolic requirements that can be targeted to restrict the enhanced proliferative and survival capacity of tumor cells while sparing normal cells (27–29). Although many studies have focused on metabolic reprogramming of tumor cells, alterations of metabolic processes in the endothelial cells that comprise the tumor vasculature have not been explored in depth (30–33). One key feature of the altered metabolism of endothelial cells is increased glycolytic flux and greater dependency on glycolysis (34,35).…”