Dual Roles of the AMP-Activated Protein Kinase Pathway in Angiogenesis

Abstract

Angiogenesis plays important roles in development, stress response, wound healing, tumorigenesis and cancer progression, diabetic retinopathy, and age-related macular degeneration. It is a complex event engaging many signaling pathways including vascular endothelial growth factor (VEGF), Notch, transforming growth factor-beta/bone morphogenetic proteins (TGF-β/BMPs), and other cytokines and growth factors. Almost all of them eventually funnel to two crucial molecules, VEGF and hypoxia-inducing factor-1 alpha (HIF-1α) whose expressions could change under both physiological and pathological conditions. Hypoxic conditions stabilize HIF-1α, while it is upregulated by many oncogenic factors under normaxia. HIF-1α is a critical transcription activator for VEGF. Recent studies have shown that intracellular metabolic state participates in regulation of sprouting angiogenesis, which may involve AMP-activated protein kinase (AMPK). Indeed, AMPK has been shown to exert both positive and negative effects on angiogenesis. On the one hand, activation of AMPK mediates stress responses to facilitate autophagy which stabilizes HIF-1α, leading to increased expression of VEGF. On the other hand, AMPK could attenuate angiogenesis induced by tumor-promoting and pro-metastatic factors, such as the phosphoinositide 3-kinase /protein kinase B (Akt)/mammalian target of rapamycin (PI3K/Akt/mTOR), hepatic growth factor (HGF), and TGF-β/BMP signaling pathways. Thus, this review will summarize research progresses on these two opposite effects and discuss the mechanisms behind the discrepant findings.

Association between excessive chronic iodine exposure and the occurrence of papillary thyroid carcinoma

“…However, only high levels of iodine were able to upregulate the expression of vascular endothelial growth factor (VEGF)-A in W3 cells (21), MAPK in TPC-1 cells (22), and AKT in TFC (thyroid follicular cells) (23). AKT and MAPK are involved in the PI3K/AKT/mTOR and MAPK signaling pathways, respectively (24,25); both activate downstream VEGF (26,27), which is responsible for angiogenic activation and immune microenvironment disorders in carcinomas (27,28), contributing to proliferation and metastasis (29)(30)(31)(32)(33)(34)(35). It was therefore hypothesized that only high concentrations of iodine can trigger the activation of the PI3K/AKT/mTOR and MAPK pathways and alter VEGF-mediated angiogenesis and immune reactions, thereby promoting the proliferation and metastasis of PTC.…”

Exploring the Mechanism of Action Compound-Xueshuantong Capsule in Diabetic Retinopathy Treatment Based on Network Pharmacology

“…The main physiological function of HIF- α is to upregulate its expression under hypoxia so as to maintain the stability of systemic, local, and intracellular oxygen concentration. Studies have confirmed that angiogenesis plays an important role in diabetic retinopathy, and hypoxia-inducible factor-1 α is an important transcriptional activator of vascular endothelial growth factor [ 47 ]. HIF antagonist has a significant inhibitory effect on ocular neovascularization [ 48 ], which also proves the important role of HIF-1 in pathological neovascularization.…”

The Role of Vitamin D in Modulating Mesenchymal Stem Cells and Endothelial Progenitor Cells for Vascular Calcification

“…The activated VEGF was shown to modulate matrix metalloproteinase-9 (MMP-9) activity and increase the mobilization of EPCs [76]. In physiological hypoxia, angiogenesis was shown to repair a damaged endothelium by promoting the differentiation of EPCs [77]. The circulating EPCs migrated and invaded the subendothelial region to replace injured endothelial cells and regulated the differentiation of the surrounding stromal cells [78].…”