Angio-modulation in endothelial cells: an unexpected role of desmoglein-2 in regulating actin dynamics and its relevance to angiogenesis deregulation in systemic sclerosis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE21547 | GEO | 2012/10/01
SECONDARY ACCESSION(S): PRJNA126213
REPOSITORIES: GEO
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Project description:Gene expression study of DSG2 silenced human microvascular endothelial cells Affymetrix GeneChip Human Genome U133 Plus 2.0 Array were used to examine differentially expressed genes between normal microvascular endothelial cells and DSG2 silenced microvascular endothelial cells
2012-10-01 | E-GEOD-21547 | biostudies-arrayexpress
Project description:BackgroundThe inability of endothelial cells of patients affected by the diffuse form of Systemic sclerosis (SSc) to perform angiogenesis is a marker of the disease. We previously demonstrated that desmoglein-2 reduction is a major difference between (SSc)-microvascular endothelial cells (MVECs) and normal (N)-MVECs. Here we investigated the role of desmoglein-2 in human N-MVECs and SSc-MVECs angiogenesis.Methodology/principal findingsAngiogenesis was studied by Matrigel invasion, capillary morphogenesis in vitro and Matrigel plug assay in vivo. Gene profiling was studied by Affymetrix technology and signal transduction by Western blotting. Colocalization was validated by immunoprecipitation and confocal microscopy. SiRNAs were used to validate the roles of specific molecules. We observed that desmoglein-2 co-localizes with integrin-beta8 in N-MVECs. This complex is required to signal through Rac, FAK, SMAD1/5 and MAP-kinases, promoting an angiogenic program. Inhibition of desmoglein-2 by DSG2-siRNA impaired actin stress fibres formation, capillary morphogenesis in vitro and angiogenesis in vivo. Transcriptome profiling after DSG2 inhibition revealed alterations of several genes involved in actin organization. siRNA inhibition of integrin-beta8 and RAC2 also resulted into capillary morphogenesis impairment in N-MVECs, due to reduced expression of the same actin-assembly genes that were down-regulated by DSG2 silencing. SSc-MVECs showed down-regulation of the same genes in DSG2-siRNA treated N-MVECs, suggesting that impairment of desmoglein-2/integrin-beta8 complex contributes to angiogenesis derangement in SSc. Transfection of DSG2 in SSc-MVEC partially restored their angiogenic properties in vitro.Conclusions/significanceWe have shown that impairment of actin assembly as a result of desmoglein-2/integrin-beta8 complex formation is a major factor contributing to angiogenesis deregulation in Systemic sclerosis.
| S-EPMC3708925 | biostudies-literature
Project description:Our recently generated transgenic mouse model in which Dsg2 is overexpressed in the epidermis observed notable epidermal hyperplasia. We described how Dsg2 altered a number of genes important in epithelial cell growth including the cysteine protease inhibitor cystatin A. We offer a novel pathway of cystatin A regulation involving Dsg2 and a potential crosstalk between Dsg2 and CSTA that modulates cell adhesion.
2014-10-30 | GSE62814 | GEO
Project description:Systemic sclerosis is a chronic autoimmune connective tissue disease characterized by vascular injury and fibrosis and by an impaired angiogenesis which cannot ensure an efficient vascular recovery. Vascular injury is responsible for hypoxia and tissual ischemia which are the primary triggers for angiogenesis and are not able to induce a compensatory angiogenesis. This review article is focused on current knowledge on the mechanisms responsible for angiogenesis dysregulation in systemic sclerosis.
| S-EPMC5534276 | biostudies-literature
Project description:Patients with the diffuse avascular form of Systemic Sclerosis (SSc) and healthy controls (N) were used as sources of microvascular endothelial cells (MVEC). MVEC were obtained from biopsies of involved skin of the hands in 6 SSc patients and from 6 healthy patients undergoing surgery for traumatic events at the hands. The controls were matched by age and sex to the SSc cases. All patients fulfilled the American College of Rheumatology criteria for SSc, as well as the criteria for the diffuse form of the disease.
2005-08-30 | E-MEXP-417 | biostudies-arrayexpress
Project description:Liver involvement in systemic sclerosis (SSc) is rare. We evaluated the prevalence of liver fibrosis and hepatic autoimmunity in SSc patients in a retrospective observational cohort (97 SSc or mixed connective tissue disease with sclerodermic manifestations patients undergoing transient elastography, evaluating liver stiffness (LS) and controlled attenuation parameter (CAP), due to clinical indications along with biochemistry assessments and major antibodies associated to liver autoimmunity). Among them, 11 had LS ≥ 7.5 kPa and 5 showed an LS compatible with cirrhosis (LS ≥ 12.5 kPa). Predictors of LS ≥ 7.5 fibrosis were alcohol consumption (>14 or >7 alcoholic units/week for men and women, respectively), waist circumference (>102 or >88 cm for men and women, respectively), elevated alkaline phosphatase, and anti-La and anti-mitochondrial antibody (AMA) positivity. Six patients had CAP values compatible with severe steatosis (≥280 dB/m). Waist circumference, body mass index and diabetes mellitus were significant predictors of steatosis. Out of 97 patients, 19 were positive for AMA, 4 for anti-Sp100, 1 for anti-Gp210 and 7 were diagnosed with primary biliary cholangitis. Among SSc patients, hepatic fibrosis biomarkers and AMA prevalence are relatively high, suggesting the opportunity of performing a transient elastography and a screening for hepatic autoimmunity at diagnosis and/or during disease progression.
| S-EPMC8879679 | biostudies-literature
Project description:We studied how loss of the desmosome associated protein, desmoglein-2 (Dsg2), in the heart leads to Arrhythmogenic Cardiomyopathy with particular interest in the early stages of disease progression. Mice expressing the cardiac αMHC-Cre promoter were crossed with Dsg2 floxed mice in which exon 4-5 of the Dsg2 gene was flanked by loxP sites, resulting in Cre-mediated excision of Dsg2 in cardiac myocytes. Wild type Dsg2+/+ (Cre-, Dsg2flx/flx) and knockout Dsg2-/- (Cre+, Dsg2flx/flx) mice were generated. RNA-seq was performed on heart tissue obtained from wild-type and Dsg2-/- mice at 2-weeks and 10-weeks of age.
2021-07-22 | GSE153124 | GEO
Project description:Transcriptomic analysis of DSG2-W2A mouse heart tissue. In DSG2-W2A mice, adhesion of the desmosomal molecule desmoglein-2 (DSG2) is abrogated via mutation of its’ major interaction mechanism (so-called "tryptophan swap" (Harrison, Brasch et al. 2016)). Adult DSG2-W2A mut/mut mice resemble the phenotype of Arrhythmogenic Cardiomyopathy (ACM or ARVC) with biventricular fibrosis, impaired systolic output function and arrhythmia. This phenotype was present in mutant mice analysed at the age of 9 weeks compared to 5-days old hearts, which showed no morphological alterations.
2022-12-05 | GSE181868 | GEO
Project description:IntroductionObliterative vasculopathy and fibrosis are hallmarks of systemic sclerosis (SSc), a severe systemic autoimmune disease. Bone marrow-derived mesenchymal stromal cells (MSCs) from SSc patients may harbor disease-specific abnormalities. We hypothesized disturbed vascular smooth muscle cell (VSMC) differentiation with increased propensity towards myofibroblast differentiation in response to SSc-microenvironment defining growth factors and determined responsible mechanisms.MethodsWe studied responses of multipotent MSCs from SSc-patients (SSc-MSCs) and healthy controls (H-MSCs) to long-term exposure to CTGF, b-FGF, PDGF-BB or TGF-β1. Differentiation towards VSMC and myofibroblast lineages was analyzed on phenotypic, biochemical, and functional levels. Intracellular signaling studies included analysis of TGF-β receptor regulation, SMAD, AKT, ERK1/2 and autocrine loops.ResultsVSMC differentiation towards both, contractile and synthetic VSMC phenotypes in response to CTGF and b-FGF was disturbed in SSc-MSCs. H-MSCs and SSc-MSCs responded equally to PDGF-BB with prototypic fibroblastic differentiation. TGF-β1 initiated myofibroblast differentiation in both cell types, yet with striking phenotypic and functional differences: In relation to H-MSC-derived myofibroblasts induced by TGF-β1, those obtained from SSc-MSCs expressed more contractile proteins, migrated towards TGF-β1, had low proliferative capacity, and secreted higher amounts of collagen paralleled by reduced MMP expression. Higher levels of TGF-β receptor 1 and enhanced canonical and noncanonical TGF-β signaling in SSc-MSCs accompanied aberrant differentiation response of SSc-MSCs in comparison to H-MSCs.ConclusionsDeregulated VSMC differentiation with a shift towards myofibroblast differentiation expands the concept of disturbed endogenous regenerative capacity of MSCs from SSc patients. Disease related intrinsic hyperresponsiveness to TGF-β1 with increased collagen production may represent one responsible mechanism. Better understanding of repair barriers and harnessing beneficial differentiation processes in MSCs could widen options of autologous MSC application in SSc patients.
| S-EPMC4824407 | biostudies-literature
Project description:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown etiology. Although defects in nucleocytoplasmic transport (NCT) may be central to the pathogenesis of ALS and other neurodegenerative diseases, the molecular mechanisms modulating the nuclear pore function are still largely unknown. Here we show that genetic and pharmacological modulation of actin polymerization disrupts nuclear pore integrity, nuclear import, and downstream pathways such as mRNA post-transcriptional regulation. Importantly, we demonstrate that modulation of actin homeostasis can rescue nuclear pore instability and dysfunction caused by mutant PFN1 as well as by C9ORF72 repeat expansion, the most common mutation in ALS patients. Collectively, our data link NCT defects to ALS-associated cellular pathology and propose the regulation of actin homeostasis as a novel therapeutic strategy for ALS and other neurodegenerative diseases.
| S-EPMC6707192 | biostudies-literature