RNA-Sequencing of HDLEC treated with siRNA targeting PROX1 and TIE2
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE83299 | GEO | 2017/09/01
REPOSITORIES: GEO
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Project description:Currently, the therapeutic prospects for cirrhosis patients are limited to liver transplantation and, therefore, there is an urgent need to develop new therapeutic strategies for improved treatments. Cirrhosis was induced in male Wistar rats with CCl4 treatment, and RNA from the complete livers was extracted and quantified through microarray experiments. Angiopoietins signalling is a key pathway in blood vessel normalization. Angiopoietin 1 (Ang1)-Tie2 signalling stabilizes blood vessels, Angiopoietin 2 (Ang2) on the other hand is a context-dependent antagonist of Ang1 and decreases its stabilizing effect giving rise to immature blood vessels. Cirrhotic conditions are characterized by higher expression and activity of Ang2 than healthy conditions, resulting in the loss of blood vessels stability. Previous work showed that inhibition of Ang2 via CVX-060 enhances Ang1-Tie2 signalling, and can stabilize the vascular system in cirrhotic livers. We therefore performed RNA extraction after treatment of cirrhotic rats with CVX-060 during 4 weeks. We observed changes in expression state (expressed/not expressed) in key transcription factors previously implicated in cirrhosis.
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Project description:The ang1-Tie2 pathway is required for normal vascular development, but its molecular effectors are not well-defined during cardiac ontogeny. Here we show that endocardial specific attenuation of Tie2 results in mid-gestation lethality due to heart defects associated with a hyperplastic but simplified trabecular meshwork (fewer but thicker trabeculae). Reduced proliferation and production of endocardial cells (ECs) following endocardial loss of Tie2 results in decreased endocardial sprouting required for trabecular assembly and extension. The hyperplastic trabeculae result from enhanced proliferation of trabecular cardiomyocyte (CMs), which is associated with upregulation of Bmp10, increased retinoic acid (RA) signaling, and Erk1/2 hyperphosphorylation in the myocardium. Intriguingly, myocardial phenotypes in Tie2-cko hearts could be partially rescued by inhibiting in utero RA signaling with pan-retinoic acid receptor antagonist BMS493. These findings reveal two complimentary functions of endocardial Tie2 during ventricular chamber formation: ensuring normal trabeculation by supporting EC proliferation and sprouting, and preventing hypertrabeculation via suppression of RA signaling in trabecular CMs.
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2008-10-25 | E-GEOD-12846 | biostudies-arrayexpress
Project description:Gene expression profiles of primary lymphatic endothelial cells (LECs) isolated from human foreskin were analyzed after siRNA-mediated knockdown of control (firefly luciferase), Prox1, NR2F2 or Prox1/NR2F2 for 48 hours.
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Project description:Neurobiological consequences of traumatic brain injury (TBI) result from a complex interplay of secondary injury responses and sequela that mediates chronic disability. Endothelial cells are important regulators of the cerebrovascular response to TBI. Our work demonstrates that genetic deletion of endothelial cell (EC)-specific EPH receptor A4 (EphA4) using conditional EphA4f/f/Tie2-Cre and EphA4f/f/VE-Cadherin-CreERT2 knockout (KO) mice, promotes blood-brain barrier (BBB) integrity and tissue protection, which correlates with improved motor function and cerebral blood flow recovery following controlled cortical impact (CCI) injury. scRNAseq of capillary-derived KO ECs showed increased differential gene expression of BBB-related junctional and actin cytoskeletal regulators, namely, A-kinase anchor protein 12, Akap12, whose presence at Tie2 clustering domains is enhanced in KO microvessels. Transcript and protein analysis of CCI-injured whole cortical tissue or cortical-derived ECs suggests EphA4 limits the expression of Cldn5, Akt, and Akap12 and promotes Ang2. Blocking the Tie2 receptor using sTie2-Fc, attenuated BBB and tissue protection and reversed Akap12 mRNA and protein levels in KO compared to WT cortical-derived ECs. Conversely, direct stimulation of Tie2 using Vasculotide, an angiopoietin-1 memetic peptide, phenocopied the neuroprotection. Finally, we report a noteworthy rise in soluble Ang2 in the sera of individuals with acute TBI, highlighting its promising role as a vascular biomarker for early detection of BBB disruption. Overall, we describe a novel contribution of the axon guidance molecule, EphA4, in mediating TBI microvascular dysfunction through negative regulation of Tie2/Akap12 signaling.
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