Abstract
Healthy adipose tissue expansion and metabolism during weight gain require coordinated angiogenesis and lymphangiogenesis. These vascular growth processes rely on the vascular endothelial growth factor (VEGF) family of ligands and receptors (VEGFRs). Several studies have shown that controlling vascular growth by regulating VEGF:VEGFR signaling can be beneficial for treating obesity; however, dysregulated angiogenesis and lymphangiogenesis are associated with several chronic tissue inflammation symptoms, including hypoxia, immune cell accumulation, and fibrosis, leading to obesity-related metabolic disorders. An ideal obesity treatment should minimize adipose tissue expansion and the advent of adverse metabolic consequences, which could be achieved by normalizing VEGF:VEGFR signaling. Toward this goal, a systematic investigation of the interdependency of vascular and metabolic systems in obesity and tools to predict personalized treatment ranges are necessary to improve patient outcomes through vascular-targeted therapies. Systems biology can identify the critical VEGF:VEGFR signaling mechanisms that can be targeted to regress adipose tissue expansion and can predict the metabolic consequences of different vascular-targeted approaches. Establishing a predictive, biologically faithful platform requires appropriate computational models and quantitative tissue-specific data. Here, we discuss the involvement of VEGF:VEGFR signaling in angiogenesis, lymphangiogenesis, adipogenesis, and macrophage specification – key mechanisms that regulate adipose tissue expansion and metabolism. We then provide useful computational approaches for simulating these mechanisms, and detail quantitative techniques for acquiring tissue-specific parameters. Systems biology, through computational models and quantitative data, will enable an accurate representation of obese adipose tissue that can be used to direct the development of vascular-targeted therapies for obesity and associated metabolic disorders.
Highlights
The prevalence of obesity has tripled since 1975, affecting over 650 million adults worldwide (World Health Organization, 2018)
It would be worthwhile to study whether PDGF contributes to VEGFR signaling in obesity, as (1) PDGF is secreted by macrophages, pre-adipocytes, and adipocytes; (2) the concentration of PDGF ligands in serum and the expression of PDGF mRNA in adipose tissue cells were both shown to increase by ∼1.5× in obese mice; and (3) anti-PDGF antibody reduced endothelial tube formation compared to untreated control (Pang et al, 2008)
Because vascular endothelial growth factor (VEGF)-C can stimulate vascular permeability via binding VEGFR2, this study further suggested that VEGFR3-specific ligand (VEGF-C156S) is a more attractive choice for therapeutically activating VEGFR3 and stimulating lymphangiogenesis
Summary
The prevalence of obesity has tripled since 1975, affecting over 650 million adults worldwide (World Health Organization, 2018). It would be worthwhile to study whether PDGF contributes to VEGFR signaling in obesity, as (1) PDGF is secreted by macrophages, pre-adipocytes, and adipocytes; (2) the concentration of PDGF ligands in serum and the expression of PDGF mRNA in adipose tissue cells were both shown to increase by ∼1.5× in obese mice; and (3) anti-PDGF antibody reduced endothelial tube formation compared to untreated control (Pang et al, 2008).
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