Impaired angiogenesis and endothelial dysfunction are hallmarks of diabetes and aging. 159, 161, 183, 204), muscle atrophy (4, 105, 170), and osteoporosis (102), are often accompanied by angiogenic failure or the inadequate ability of ECs to fulfill their normally required roles (termed EC dysfunction). This dysfunction results in tissue ischemia, giving 548-37-8 IC50 rise to cardiovascular diseases or metabolic perturbations such as impaired glucose tolerance and excess lipid accumulation (lipotoxicity) (73, 75, 94, 123, 127, 161, 181). Research for the past decades has uncovered critical pro- and anti-angiogenic growth factors, most notably including vascular endothelial growth factor (VEGF; also known as VEGFA) (26, 155). To rescue ischemic tissues, therapeutic angiogenesis with VEGF and other growth factors has been explored but has shown limited success (25, 160), underscoring our still insufficient understanding of the angiogenic process. Recently, it has become clear that EC metabolism contributes to the EC angiogenic phenotype and responsiveness to angiogenic growth factors, and thereby regulates angiogenesis (36, 49, 50, 67). In addition, many players in EC metabolism are also shown to be pivotal for MLLT3 age-related processes, including the control of stress response and longevity (70, 133, 154). In this review, in the first part, we will discuss a general view of EC metabolism and (sprouting) angiogenesis, and recent insights into how the former regulates the latter. This will set up a platform for the second part, in which we discuss how EC metabolism is usually altered in diabetes and age-related disorders, and potentially mediates the vascular dysfunction and angiopathy (angiogenesis impairment) associated with these conditions. Metabolic Control of 548-37-8 IC50 Angiogenesis Unique Bioenergetics Regulation in ECs: High Dependence on Glycolysis ECs are atypical nonmalignant cells that surprisingly depend on glycolysis to synthesize >80% of ATP (35, 37). Even under well-oxygenated conditions, the glycolysis rate in ECs is usually strikingly higher than in pericytes, easy muscle cells, and any other nonvascular cell types thus far examined, and comparable to that of 548-37-8 IC50 tumor cells, many of which use aerobic glycolysis for continuous growth and expansion (known as Warburg effect). Glycolysis is usually pivotal for the homeostasis of ECs, since near-total blockage of glycolysis [e.g., by 2-deoxyglucose (2-DG)] induces cell death (37, 49, 124, 177). Unlike in many other cell types, ATP generation in ECs relies minimally on fatty acid oxidation (FAO), glutamine oxidation, or glucose oxidation, i.e., on the mitochondrial respiratory chain (37, 152). Nevertheless, mitochondria do serve as a bioenergetic source for ECs under stressed conditions. Mitochondria also regulate cellular survival by mediating calcium handling and redox status by producing a moderate level of superoxide, and provide building blocks (acetyl-CoA) for cellular anabolic needs through the tricarboxylic acid (TCA) cycle (35, 45). Within the vascular sprouts induced by angiogenic factors like VEGF, ECs upregulate glycolysis partly via increasing 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), glucose transporter 1 (GLUT-1; mediates glucose transport across the plasma membrane), and lactate dehydrogenase-A (LDH-A; catalyzes the conversion of pyruvate and NADH into L-lactate and NAD+) (37, 147, 150, 217) (FIGURE 1). PFKFB3 most potently activates glycolysis through generating fructose-2,6-bisphosphate (F2,6P2), an allosteric activator of phosphofructokinase-1 (PFK-1) (198) (FIGURE 1). Knockdown of PFKFB3 and the consequent diminution of 548-37-8 IC50 EC glycolysis in vitro decrease EC migration and proliferation, and blunt capillary sprouting from EC spheroids. Moreover, EC PFKFB3 gene ablation in vivo impedes vessel 548-37-8 IC50 sprouting, branching, and outgrowth (37). Physique 1. Normal endothelial cell metabolism Glycolysis also provides important metabolites that act as precursors for biosynthetic pathways via, for example, the pentose phosphate pathway (PPP) and hexosamine biosynthesis pathway (HBP) (FIGURE 1). The PPP harbors oxidative and non-oxidative branches. The rate of oxidative PPP is usually dictated by glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme whose activity is usually in part decided by VEGF in ECs (144). The oxidative branch (oxPPP) of the PPP synthesizes NADPH from NADP+ and thus confers reducing power to regulate cellular redox state and biosynthetic potentials (164) (as exhibited in tumor cells). Both oxidative and non-oxidative PPP branches generate ribose-5-phosphate (R5P),.