Nitric oxide promotes endothelial cell survival signaling through S-nitrosylation and activation of dynamin-2

Abstract

Endothelial cell-based angiogenesis requires activation of survival signals that generate resistance to external apoptotic stimuli, such as tumor necrosis factor-alpha (TNF-α), during pathobiologic settings. Mechanisms by which this is achieved are not fully defined. Here, we use a model in which the multifunctional cytokine nitric oxide counterbalances TNF-α-induced apoptosis, to define a role for membrane trafficking in the process of endothelial cell survival signaling. By perturbing dynamin GTPase function, we identify a key role of dynamin for ensuing downstream endothelial cell survival signals and vascular tube formation. Furthermore, nitric oxide is directly demonstrated to promote dynamin function through specific cysteine residue nitrosylation, which promotes endocytosis and endothelial cell survival signaling. Thus, these studies identify a novel role for dynamin as a survival factor in endothelial cells, through a mechanism by which dynamin S-nitrosylation regulates the counterbalances of TNF-α-induced apoptosis and nitric oxide-dependent survival signals, with implications highly relevant to angiogenesis.

Nitric Oxide Regulates Tumor Cell Cross-Talk with Stromal Cells in the Tumor Microenvironment of the Liver

“…Of course eNOS contributes to angiogenic EC signaling, 8,22 however, previous work from us and others has also demonstrated that NO limits hepatic stellate cell migration, motility, and other features of activation that lead pericytes toward a myofibroblast phenotype. 3,7 These observations led us to hypothesize that NO may have beneficial effects on tumor progression by attenuating the tumor-progressing effects of myofibroblasts and the matrix derived from these cells.…”

“…The retroviral transduction system resulted in nearly 100% transfection efficiency as we have previously described. 22 As Ϫ/Ϫ mice with myofibroblast markers such as NG2, SMA, and desmin showed positivity for the three markers. Although some co-localization was noticed between some markers many of the cells displayed only one of the markers.…”

Transcriptional Assessment by Microarray Analysis and Large-Scale Meta-analysis of the Metabolic Capacity of Cardiac and Skeletal Muscle Tissues to Cope With Reduced Nutrient Availability in Gilthead Sea Bream (Sparus aurata L.)

“…This is specially supported by the up-regulation of dynamin-2, already known as a survival factor for bovine endothelial cells (Kang-Decker et al, 2007). Conversely, the transcription activator ets variant gene 5, involved in cell growth and differentiation, was down-regulated, but even so the augmented expression of this gene is associated with several mouse cardiomyopathies (Spurney et al, 2008).…”

iNOS-Derived Nitric Oxide Induces Integrin-Linked Kinase Endocytic Lysosome-Mediated Degradation in the Vascular Endothelium

“…30 Previous studies have demonstrated that NO can stimulate endocytosis by S-nytrosilation of dynamin. 31,32 Therefore, we tested whether dynamin-mediated endocytosis was involved in NO-induced ILK degradation by using a specific inhibitor of dynamin activity, Dyngo 4a. Confocal microscopy showed that dynamin was mediating the NO-dependent internalization of ILK into endosomes.…”