The role of mitochondria in angiogenesis

Abstract

Angiogenesis extends pre-existing blood vessels to improve oxygen and nutrient delivery to inflamed or otherwise hypoxic tissues. Mitochondria are integral in this process, controlling cellular metabolism to regulate the proliferation, migration, and survival of endothelial cells which comprise the inner lining of blood vessels. Mitochondrial Complex III senses hypoxic conditions and generates mitochondrial reactive oxygen species which stabilize hypoxia-inducible factor (HIF-1α) protein. HIF-1α induces the transcription of the vegfa gene, allowing the translation of vascular endothelial growth factor protein, which interacts with mature and precursor endothelial cells, mobilizing them to form new blood vessels. This cascade can be inhibited at specific points by means of gene knockdown, enzyme treatment, and introduction of naturally occurring small molecules, providing insight into the relationship between mitochondria and angiogenesis. This review focuses on current knowledge of the overall role of mitochondria in controlling angiogenesis and outlines known inhibitors that have been used to elucidate this pathway which may be useful in future research to control angiogenesis in vivo.

Keywords: Angiogenesis; Endothelial; HIF-1α; Mitochondria; VEGF; mROS.

Fig. 1. Summary of the Angiogenesis Pathway

Ischemia, exercise, and inflammation create a hypoxic tissue environment, resulting in decreased oxygen availability in cells. Under these hypoxic conditions, the electron transport chain produces mROS at mitochondrial Complex III. These mROS exit the mitochondria and deactivate prolyl hydroxylase (PHD). Under normoxic conditions, the levels of mROS being produced are insufficient to deactivate PHD, and PHD therefore hydroxylates the HIF-1α protein, marking it for eventual degradation by proteasomes. When high levels of mROS are produced under hypoxia, HIF-1α is stabilized, allowing the production of the VEGF protein. This VEGF protein attaches to the VEGFR2 receptor on both mature endothelial cells lining blood vessels and circulating endothelial precursors (CEP). This activates the ERK and Akt pathways, causing the maturation and mobilization of endothelial cells, allowing angiogenesis to occur.