Distinct role of autophagy on angiogenesis: highlights on the effect of autophagy in endothelial lineage and progenitor cells

Abstract

Autophagy plays a critical role in the dynamic growth of each cell through different conditions. It seems that this intracellular mechanism acts as a two-edged sword against the numerous cell insults. Previously, autophagy was described in the context of cell activity and behavior, but little knowledge exists related to the role of autophagy in endothelial cells, progenitors, and stem cells biology from different tissues. Angiogenic behavior of endothelial lineage and various stem cells are touted as an inevitable feature in the restoration of different damaged tissues and organs. This capacity was found to be dictated by autophagy signaling pathway. This review article highlights the fundamental role of cell autophagic response in endothelial cells function, stem cells dynamic, and differentiation rate. It seems that elucidation of the mechanisms related to pro- and/or anti-angiogenic potential of autophagy inside endothelial cells and stem cells could help us to modulate stem cell therapeutic feature post-transplantation.

Keywords: Angiogenesis; Autophagy; Differentiation; Functional maturation; Stem cell.

Fig. 1

Autophagy is classified into three types based on the route of delivery. Microautophagy refers to the sequestration of misfunction proteins or whole organelles such as mitochondria (named mitophagy) directly by lysosomes. Chaperone-mediated autophagy (CMA) involves direct translocation of misfolded substrates across the lysosome membrane through the action of a cytosolic and lysosomal chaperone hsc70, and the integral membrane receptor LAMP-2A (lysosome-associated membrane protein type 2A). In the case of macroautophagy, the cargoes are sequestered within a unique double-membrane cytosolic vesicle, named autophagosome. This type of autophagy is initiated by the nucleation of an isolation membrane or phagophore. ULK, ATG 13, FIP200, and ATG101 are involved in this stage. Then, the Beclin-1 and ATG14L complex contributes to the nucleation of the phagophore. This membrane then elongates and closes on itself to form an autophagosome. Elongation of the phagophore membrane is dependent on the Atg12 and LC3 conjugation systems. Closure of the autophagosome is dependent on the activity of the LC3-conjugation system. The autophagosome matures by fusing with endosomes and lysosomes, finally forming the autophagolysosome where the cargo degradation occurs

Fig. 2

Representative image of the anti-angiogenic potential of autophagy. Anti-angiogenic effect autophagy is initiated via the modulation of Wnt/β-catenin axis. The application of autophagy inducer, magnolol (Ery5), has an inhibitory effect on migration and tube formation properties in both human umbilical vein endothelial cells and apoptotic resistant cancer cells while chemical blocking of autophagy by 3-MA or gene silencing of Atg7 and LC3 reversed anti-angiogenic effect of autophagy VEGFR-2 levels and angiogenesis are reduced following endothelial dysfunction and exposure to advanced glycation end products (AGEs) accumulation under diabetic condition. Autophagy plays a key role in VEGFR-2 degradation and impaired angiogenesis. Gastrin-releasing peptide (GRP) and its receptor GRPR through PI3K-AKT pathway have a pivotal role in cancer-related angiogenesis. By antagonizing GRPR, pro-autophagic proteins are overexpressed and angiogenesis blocked by autophagy-mediated GRP degradation mechanism

Fig. 3

Angiogenic potential of autophagy. Starvation-induced autophagy triggers cell migration and in vitro angiogenesis by activating of VEGF and AKT protein on ECs. AGGF1-induced autophagy is a candidate for coronary artery disease and myocardial infarction treatment. Chemerin, a novel adipose tissue cytokine, also has a stimulatory effect on retinal endothelial cells angiogenesis by promoting autophagy activity and expression of the autophagy-related proteins LC3 and Beclin-1 increased during chemerin-induced migration and tubular formation