Autophagy in endothelial cells and tumor angiogenesis

Autophagy induction during metabolic stress and its proposed functions beyond (targeted) lysosomal degradation in endothelial cells. Autophagy and its related proteins are implicated in additional cellular processes that control endothelial cell (EC) behavior. At least in part this may be due to the close interplay of autophagy machinery with components of the endo-lysosomal system. Yet, it must be noted that both autophagy and endosomes/lysosomes also control distinct processes as will be clarified throughout this review. Top left: basal level activity of autophagy is stimulated upon metabolic stresses that induce signaling events to increase the formation of the initial cup-shaped membrane called a phagophore (nucleation). At the phagophore membrane, a complex consisting of class III PI3K, VPS34, and Beclin1 (BECN1) generates PI3P, thereby facilitating recruitment of the ATG12-ATG5-ATG16L complex. The latter facilitates the conjugation of LC3B (or other family members) to phosphatidylethanolamine (PE) for membrane anchoring of this key autophagy marker. Metabolic stressors (e.g. hypoxia, causing stabilization of hypoxia-inducible factor (HIF), glucose deprivation, leading to activation of AMPK and inhibition of mTOR) stimulate autophagy in ECs. HIF induces expression of BNIP3 that competes with BECN1 for BCL2 interaction thereby releasing BECN1. Reduced activity of mTORC1 relieves ULK1 complex from inhibition that can subsequently induce autophagy. (Diagonal) The phagophore further elongates to form a closed autophagosome, which engulfs cytoplasmic constituents (non)specifically. After fusion with a lysosome, the autophagosomal content is degraded releasing metabolites that are recycled by the cell. Bottom left: a connection between autophagosomes and multivesicular bodies (collection of luminal vesicles) exists in which fusion events generate a so called amphisome. Top middle: autophagy as well as lysosomal machinery are required for proper formation of Weibel–Palade bodies (storage/secretory granules of ECs). Top right: in addition, key autophagy proteins and autophagosomes are implicated in unconventional secretion of proteins, which bypasses the classical endoplasmic reticulum-to-Golgi route. Here autophagy may serve as a vesicular mechanism for protein transport across the plasma membrane or receptor trafficking for cell surface localization. Right: endosomal vesicles regulate receptor cell surface localization as well as protein secretion event