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.

High Triglycerides Are Associated with Low Thrombocyte Counts and High VEGF in Nephropathia Epidemica

“…VEGF can play dual role in regulating endothelial integrity. For example, VEGF can be protective, promoting endothelial cell survival [30, 42]. However, VEGF can also increase endothelial permeability and promote vascular leakage [43].…”

Остеопонтин Та Остеокальцин При Раку Легенів

“…Необходимо отметить, что наряду с VEGF ОР уча-ствует в процессах ракового ангиогенеза, причем оба этих маркера между собой тесно прямо коррелируют, а одновременное увеличение в организме ОР и VEGF относится к факторам неблагоприятного течения РЛ [4,10]. VEGF признан одним из важнейших промото-ров ангиогенеза в опухоли легкого, который связыва-ется со специфическими рецепторами и стимулирует формирование кровеносных сосудов, их рост и про-ницаемость.…”

“…Имели место прямые корреляционные связи ОР и ОС (r = +0,21, p = 0,02), а также ОР с VEGF (r = +0,24, p = 0,01), тогда как соотношения VEGF и OC оказались недостовер-ными (рис. 4,5).…”

Context‐dependent regulation of receptor tyrosine kinases: Insights from systems biology approaches

“…For example, while cell‐autonomous VEGF signaling is not necessary for angiogenesis, it is essential for vascular homeostasis in mice, and paracrine VEGF cannot compensate for its loss (Lee et al, ). A later study revealed that autocrine VEGF inhibits mitochondria fragmentation and maintains glucose metabolism, thus preventing autophagy‐induced cell death (Domigan et al, ).…”