Angiogenesis revisited – role and therapeutic potential of targeting endothelial metabolism

Abstract

Clinically approved therapies that target angiogenesis in tumors and ocular diseases focus on controlling pro-angiogenic growth factors in order to reduce aberrant microvascular growth. Although research on angiogenesis has revealed key mechanisms that regulate tissue vascularization, therapeutic success has been limited owing to insufficient efficacy, refractoriness and tumor resistance. Emerging concepts suggest that, in addition to growth factors, vascular metabolism also regulates angiogenesis and is a viable target for manipulating the microvasculature. Recent studies show that endothelial cells rely on glycolysis for ATP production, and that the key glycolytic regulator 6-phosphofructo-2-kinase/ fructose-2,6-bisphosphatase 3 (PFKFB3) regulates angiogenesis by controlling the balance of tip versus stalk cells. As endothelial cells acquire a tip cell phenotype, they increase glycolytic production of ATP for sprouting. Furthermore, pharmacological blockade of PFKFB3 causes a transient, partial reduction in glycolysis, and reduces pathological angiogenesis with minimal systemic harm. Although further assessment of endothelial cell metabolism is necessary, these results represent a paradigm shift in anti-angiogenic therapy from targeting angiogenic factors to focusing on vascular metabolism, warranting research on the metabolic pathways that govern angiogenesis.

Comparative systems pharmacology of HIF stabilization in the prevention of retinopathy of prematurity

“…S3). Aerobic glycolysis is reported to drive endothelial growth and repair as a stimulus for DL4/Notch-dependent endothelial tip cell sprouting (43,44). Our analysis found multiple glycolytic genes up-regulated by Roxadustat in the retina (Fig.…”

Targeting of MCT1 and PFKFB3 influences cell proliferation and apoptosis in bladder cancer by altering the tumor microenvironment

“…4). The possible reason may be that silencing of MCT1 or/and PFKFB blocked the main energy metabolic pathway, which accounts for ~85% of the energy of ECs (25).…”

A novel biodegradable self-healing hydrogel to induce blood capillary formation

“…32 Previous research has indicated that ECs enhance their glycolysis, thus inducing vasculogenesis. 33 Moreover, mitochondrial respiration triggers the EC apoptosis, which is associated with vessel regression, thus providing a crucial balance to EC proliferation during angiogenesis. 33 We directly evaluated the metabolism (glycolysis and mitochondrial respiration) of ECs that were encapsulated in each gel by the bioenergetic assay.…”

“…33 Moreover, mitochondrial respiration triggers the EC apoptosis, which is associated with vessel regression, thus providing a crucial balance to EC proliferation during angiogenesis. 33 We directly evaluated the metabolism (glycolysis and mitochondrial respiration) of ECs that were encapsulated in each gel by the bioenergetic assay. Analysis of the extracellular acidification rate with a Seahorse XF Flux Analyzer revealed the basal glycolysis levels of the cells.…”