Abstract
Angiogenesis is the process of new blood vessel formation. In this complex orchestrated growth, many factors are included. Lately, focus has shifted to endothelial cell metabolism, particularly to the PFKFB3 protein, a key regulatory enzyme of the glycolytic pathway. A variety of inhibitors of this important target have been studied, and a plethora of biological effects related to the process of angiogenesis have been reported. However, recent studies have disputed their mechanism of action, questioning whether all the effects are indeed due to PFKFB3 inhibition. Remarkably, the most well-studied inhibitor, 3PO, does not bind to PFKFB3, raising questions about this target. In our study, we aimed to elucidate the effects of PFKFB3 inhibition in angiogenesis by using the small molecule AZ67. We used isothermal titration calorimetry and confirmed binding to PFKFB3. In vitro, AZ67 did not decrease lactate production in endothelial cells (ECs), nor ATP levels, but exhibited good inhibitory efficacy in the tube-formation assay. Surprisingly, this was independent of EC migratory and proliferative abilities, as this was not diminished upon treatment. Strikingly however, even the lowest dose of AZ67 demonstrated significant inhibition of angiogenesis in vivo. To our knowledge, this is the first study to demonstrate that the process of angiogenesis can be disrupted by targeting PFKFB3 independently of glycolysis inhibition.
Highlights
Angiogenesis is the growth of new blood vessels from preexisting vasculature
By using isothermal titration calorimetry, we demonstrated binding of AZ67 to PFKFB3
[35], we calorimetry, aimed to demonstrate that AZ67 binds to PFKFB3
Summary
It is a complex multifaceted process that is critical for many physiological and pathological conditions such as embryonic development, wound repair, inflammation, and tumor growth [1]. In this dynamic process, the proliferation and migration of ECs and the recruitment of pericytes play a central role, constructing a vascular tube that is oriented toward the site that requires oxygen and nutrient supply [2]. Adult ECs remain largely in a quiescent state, but can become rapidly activated in response to pathological conditions In these conditions, e.g., injury, where the formation of new blood vessels is required, the process of angiogenesis is activated. Three main EC subtypes govern the process of angiogenesis: migratory tip cells, which are specialized in growing vascular sprouts in response to growth factors; stalk cells, which proliferate and elongate the sprout; and quiescent phalanx cells, mostly present in established vessels and are responsible for maintaining vascular homeostasis and endothelial barrier function [3,4,5]
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