Autocrine VEGF maintains endothelial survival through regulation of metabolism and autophagy

Abstract

Autocrine VEGF is necessary for endothelial survival, although the cellular mechanisms supporting this function are unknown. Here, we show that -even after full differentiation and maturation -continuous expression of VEGF by endothelial cells is needed to sustain vascular integrity and cellular viability. Depletion of VEGF from the endothelium results in mitochondria fragmentation and suppression of glucose metabolism, leading to increased autophagy that contributes to cell death. Gene-expression profiling showed that endothelial VEGF contributes to the regulation of cell cycle and mitochondrial gene clusters, as well as several -but not all -targets of the transcription factor FOXO1. Indeed, VEGF-deficient endothelium in vitro and in vivo showed increased levels of FOXO1 protein in the nucleus and cytoplasm. Silencing of FOXO1 in VEGF-depleted cells reversed expression profiles of several of the gene clusters that were de-regulated in VEGF knockdown, and rescued both cell death and autophagy phenotypes. Our data suggest that endothelial VEGF maintains vascular homeostasis through regulation of FOXO1 levels, thereby ensuring physiological metabolism and endothelial cell survival.

Hypoxia-Preconditioned Adipose-Derived Stem Cells Combined with Scaffold Promote Urethral Reconstruction by Up-Regulation of Angiogenesis and Glycolysis

“…VEGFA is one of the most important vascularization-related factors and plays a vital role in vascularization and tissue engineering [23]. It has also been reported that VEGFA can increase glycolysis and ensure physiological metabolism [20,36]. There is consensus that VEGFR-2 is the main receptor of VEGFA that plays an angiogenic role via tyrosine phosphorylation [31].…”

Would intravitreal bevacizumab injection increase risk of cerebral infarction?

“…The half-life in the systemic circulation after intravitreal injection is much longer for bevacizumab and aflibercept than for ranibizumab, probably due to the absence of an Fc component in the case of ranibizumab [27]. VEGF is necessary for normal functioning of the endothelium, in that it promotes vascular integrity and endothelial cell survival [28,29] but, in one study, systemic anti-VEGF agents caused vascular endothelial cell dysfunction, which induced a coagulation cascade [30]. Some VEGF isoforms play a positive role in cardiovascular function, but non-selective inhibition of VEGF may be involved in the induction of thromboembolic events [31].…”

Vascular endothelial growth factor‐D modulates oxidant–antioxidant balance of human vascular endothelial cells

“…These VEGF-D effects were confirmed in our further analysis in the presence of the oxidative stress inducers NaClO and paraquat and are consistent with recent studies that found VEGF-A to be instrumental for EC protection induced by ROS. Moreover VEGF-D may up-regulate expression of antioxidant system proteins not only for cell protection from oxidative stress but also to use them as secondary messengers [38,39].…”