Mechanistic insight into activation of MAPK signaling by pro-angiogenic factors

Abstract

BackgroundAngiogenesis is important in physiological and pathological conditions, as blood vessels provide nutrients and oxygen needed for tissue growth and survival. Therefore, targeting angiogenesis is a prominent strategy in both tissue engineering and cancer treatment. However, not all of the approaches to promote or inhibit angiogenesis lead to successful outcomes. Angiogenesis-based therapies primarily target pro-angiogenic factors such as vascular endothelial growth factor-A (VEGF) or fibroblast growth factor (FGF) in isolation. However, pre-clinical and clinical evidence shows these therapies often have limited effects. To improve therapeutic strategies, including targeting FGF and VEGF in combination, we need a quantitative understanding of the how the promoters combine to stimulate angiogenesis.ResultsIn this study, we trained and validated a detailed mathematical model to quantitatively characterize the crosstalk of FGF and VEGF intracellular signaling. This signaling is initiated by FGF binding to the FGF receptor 1 (FGFR1) and heparan sulfate glycosaminoglycans (HSGAGs) or VEGF binding to VEGF receptor 2 (VEGFR2) to promote downstream signaling. The model focuses on FGF- and VEGF-induced mitogen-activated protein kinase (MAPK) signaling and phosphorylation of extracellular regulated kinase (ERK), which promotes cell proliferation. We apply the model to predict the dynamics of phosphorylated ERK (pERK) in response to the stimulation by FGF and VEGF individually and in combination. The model predicts that FGF and VEGF have differential effects on pERK. Additionally, since VEGFR2 upregulation has been observed in pathological conditions, we apply the model to investigate the effects of VEGFR2 density and trafficking parameters. The model predictions show that these parameters significantly influence the response to VEGF stimulation.ConclusionsThe model agrees with experimental data and is a framework to synthesize and quantitatively explain experimental studies. Ultimately, the model provides mechanistic insight into FGF and VEGF interactions needed to identify potential targets for pro- or anti-angiogenic therapies.Electronic supplementary materialThe online version of this article (10.1186/s12918-018-0668-5) contains supplementary material, which is available to authorized users.

ERK/MAPK signalling pathway and tumorigenesis (Review)

“…Tumour angiogenesis involves not only the overexpression of angiogenic factors, but also the low expression of angiogenic inhibitors and an imbalance between the two (118). VEGF is an important pro-angiogenic factor and the most powerful pro-vascular endothelial growth cytokine that promotes cell division and vascular construction from esophageal cancer and ovarian cancer, increases microvascular permeability and promotes endothelial cell migration (119)(120)(121).…”

Peroxisome Proliferator-Activated Receptor γ Coactivator 1α Activates Vascular Endothelial Growth Factor That Protects Against Neuronal Cell Death Following Status Epilepticus through PI3K/AKT and MEK/ERK Signaling

“…VEGF/VEGFR2 activates the MEK/ERK signaling pathway as evidenced by an increase in ERK and MEK phosphorylation levels [ 36 , 37 ]. To determine the regulatory role of VEGE/VEGFR2 in the MEK/ERK pathway, we examined the protein levels of phosphorylated ERK (p-ERK) and MEK (p-MEK), and total ERK and MEK.…”

Sturge-Weber Syndrome and Haematuria: a Case Report of an Unusual Presentation

“…Further abnormalities in cerebral vasculature can include calcium deposition and increased endothelial proliferation [3,15]. Given that vascularendothelial growth factor (VEGF) and its associated receptor are heavily expressed in both cerebral vasculature and renal vasculature, and that GNAQ mutations increase downstream signalling in VEGF and mitogen-activated protein kinase (MAPK) pathways, it stands to reason that these malformations and abnormalities might also be present in the renal arterial system and hence cause the infarct [15,23,24]. Hence, CT angiography of the renal vasculature should be worth pursuing in patients with renal infarcts and SWS.…”