ABSTRACT
Notch signaling is a core patterning module for vascular morphogenesis that codetermines the sprouting behavior of endothelial cells (ECs). Tight quantitative and temporal control of Notch activity is essential for vascular development, yet the details of Notch regulation in ECs are incompletely understood. We found that ubiquitin-specific peptidase 10 (USP10) interacted with the NOTCH1 intracellular domain (NICD1) to slow the ubiquitin-dependent turnover of this short-lived form of the activated NOTCH1 receptor. Accordingly, inactivation of USP10 reduced NICD1 abundance and stability and diminished Notch-induced target gene expression in ECs. In mice, the loss of endothelial Usp10 increased vessel sprouting and partially restored the patterning defects caused by ectopic expression of NICD1. Thus, USP10 functions as an NICD1 deubiquitinase that fine-tunes endothelial Notch responses during angiogenic sprouting.
Subject(s)
Endothelium, Vascular/metabolism , Neovascularization, Physiologic/physiology , Proteolysis , Receptor, Notch1/metabolism , Ubiquitin Thiolesterase/physiology , Animals , HEK293 Cells , Human Umbilical Vein Endothelial Cells , Humans , Mice , Mice, Knockout , Neovascularization, Physiologic/genetics , Protein Domains , Protein Stability , RNA, Small Interfering/genetics , Signal Transduction , Ubiquitin Thiolesterase/geneticsABSTRACT
We report a case of a 37-year-old patient presenting with fulminant cardiogenic shock, almost noncontractile ventricles, followed by electromechanical dissociation. During performance of cardiopulmonary resuscitation, a veno-arterial extracorporeal membrane oxygenation device (VA ECMO) was implanted, which became necessary for 13 days. Subsequently, a total arrest of ventricular function was observed and prominent multiple organ failure emerged. A rapid test for respiratory syncytial virus was positive, supporting the suspected diagnosis of myocarditis. Despite numerous complications, complete recovery was achieved.
Subject(s)
Extracorporeal Membrane Oxygenation/methods , Intensive Care Units , Myocarditis/therapy , Shock, Cardiogenic/therapy , Adult , Disease Progression , Echocardiography , Electrocardiography , Female , Follow-Up Studies , Heart Arrest/therapy , Humans , Hypothermia, Induced/methods , Kidney Function Tests , Length of Stay , Liver Function Tests , Multiple Organ Failure/diagnosis , Multiple Organ Failure/therapy , Myocarditis/diagnosis , Renal Dialysis/methods , Respiratory Syncytial Virus Infections/diagnosis , Respiratory Syncytial Virus Infections/therapy , Resuscitation/methods , Shock, Cardiogenic/diagnosis , Signal Processing, Computer-AssistedABSTRACT
In most arterial beds a significant endothelium-dependent dilation to various stimuli persists even after inhibition of nitric oxide synthase and cyclo-oxygenase. This dilator response is preceded by an endothelium-dependent hyperpolarization of vascular smooth muscle cells, which is sensitive to a combination of the calcium-dependent potassium-channel inhibitors charybdotoxin and apamin, and is assumed to be mediated by an unidentified endothelium-derived hyperpolarizing factor (EDHF). Here we show that the induction of cytochrome P450 (CYP) 2C8/34 in native porcine coronary artery endothelial cells by beta-naphthoflavone enhances the formation of 11,12-epoxyeicosatrienoic acid, as well as EDHF-mediated hyperpolarization and relaxation. Transfection of coronary arteries with CYP 2C8/34 antisense oligonucleotides results in decreased levels of CYP 2C and attenuates EDHF-mediated vascular responses. Thus, a CYP-epoxygenase product is an essential component of EDHF-mediated relaxation in the porcine coronary artery, and CYP 2C8/34 fulfils the criteria for the coronary EDHF synthase.