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

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-beta/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-1 alpha) whose expressions could change under both physiological and pathological conditions. Hypoxic conditions stabilize HIF-1 alpha, while it is upregulated by many oncogenic factors under normaxia. HIF-1 alpha 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-1 alpha, 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-beta/BMP signaling pathways. Thus, this review will summarize research progresses on these two opposite effects and discuss the mechanisms behind the discrepant findings.