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Loss of Pim1 Imposes a Hyperadhesive Phenotype on Endothelial Cells

ABSTRACT: Background: PIM1 is a constitutively active serine-threonine kinase regulating cell survival and proliferation. Increased PIM1 expression has been correlated with cancer metastasis by facilitating migration and anti-adhesion. Endothelial cells play a pivotal role in these processes by contributing a barrier to the blood stream. Here, we investigated whether PIM1 regulates mouse aortic endothelial cell (MAEC) monolayer integrity. Methods: Pim1-/-MAEC were isolated from Pim1 knockout mice and used in trypsinization-, wound closure assays, electrical cell-substrate sensing, immunostaining, cDNA transfection and as RNA source for microarray analysis. Results: Pim1-/-MAEC displayed decreased migration, slowed cell detachment and increased electrical resistance across the endothelial monolayer. Reintroduction of Pim1- cDNA into Pim1-/-MAEC significantly restored wildtype adhesive characteristics. Pim1-/--MAEC displayed enhanced focal adhesion and adherens junction structures containing vinculin and β-catenin, respectively. Junctional molecules such as Cadherin 13 and matrix components such as Collagen 6a3 were highly upregulated in Pim1-/- cells. Intriguingly, extracellular matrix deposited by Pim1-/- cells alone was sufficient to induce the hyperadhesive phenotype in wildtype endothelial cells. Conclusion: Loss of Pim1 induces a strong adhesive phenotype by enhancing endothelial cell-cell and cell-matrix adhesion by the deposition of a specific extracellular matrix. Targeting PIM1 function therefore might be important to promote endothelial barrier integrity.

ORGANISM(S): Mus musculus

PROVIDER: GSE32059 | GEO | 2012/10/29

SECONDARY ACCESSION(S): PRJNA147619

REPOSITORIES: GEO

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Loss of Pim1 Imposes a Hyperadhesive Phenotype on Endothelial Cells

Project description:Background: PIM1 is a constitutively active serine-threonine kinase regulating cell survival and proliferation. Increased PIM1 expression has been correlated with cancer metastasis by facilitating migration and anti-adhesion. Endothelial cells play a pivotal role in these processes by contributing a barrier to the blood stream. Here, we investigated whether PIM1 regulates mouse aortic endothelial cell (MAEC) monolayer integrity. Methods: Pim1-/-MAEC were isolated from Pim1 knockout mice and used in trypsinization-, wound closure assays, electrical cell-substrate sensing, immunostaining, cDNA transfection and as RNA source for microarray analysis. Results: Pim1-/-MAEC displayed decreased migration, slowed cell detachment and increased electrical resistance across the endothelial monolayer. Reintroduction of Pim1- cDNA into Pim1-/-MAEC significantly restored wildtype adhesive characteristics. Pim1-/--MAEC displayed enhanced focal adhesion and adherens junction structures containing vinculin and M-NM-2-catenin, respectively. Junctional molecules such as Cadherin 13 and matrix components such as Collagen 6a3 were highly upregulated in Pim1-/- cells. Intriguingly, extracellular matrix deposited by Pim1-/- cells alone was sufficient to induce the hyperadhesive phenotype in wildtype endothelial cells. Conclusion: Loss of Pim1 induces a strong adhesive phenotype by enhancing endothelial cell-cell and cell-matrix adhesion by the deposition of a specific extracellular matrix. Targeting PIM1 function therefore might be important to promote endothelial barrier integrity. Pim-1-/- mouse aortic endothelial cells were compared to wildtype cells

2012-10-29 | E-GEOD-32059 | biostudies-arrayexpress

Transcriptome profiles of control and PIM1 over-expressing LNCaP cells in complete media

Project description:We used control and PIM1 over-expressing LNCaP cells to analyze the effect of PIM1 on gene expression. We find that PIM1 over-expression results in up- and down-regulation of different classes of genes, including increasing gene expression involved in extracellular matrix organization, cell adhesion, and cytokine signaling.

2021-11-03 | GSE181225 | GEO

A Novel Role for A20-Regulated CNS Endothelial ICOSL in Immune Cell Adhesion and Autoimmune Neuroinflammation

Project description:A20 is a ubiquitin-modifying protein that negatively regulates canonical NF-κB signaling and mutations in A20/TNFAIP3 have been associated with a variety of autoimmune diseases, including multiple sclerosis (MS). We found that deletion of A20 in central nervous system (CNS) endothelial cells (BEC) enhances experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. These mice showed increased numbers of CNS-infiltrating immune cells during neuroinflammation and in the steady state. While the integrity of the barrier was not impaired, we observed a strong activation of the endothelium in A20ΔBEC mice, with dramatically increased levels of the adhesion molecules ICAM-1 and VCAM-1. We furthermore discovered ICOSL as novel adhesion molecule expressed by A20-deficient BECs. Silencing of ICOSL in BECs ameliorated the severity of an active EAE disease in wildtype mice and significantly delayed the onset of symptom development. Furthermore, blocking of ICOSL on primary CNS-derived endothelial cells impaired the adhesion of different T cell populations to the monolayer. Taken together, we here report a novel function of A20-regulated ICOSL expressed on CNS endothelial cells during inflammation. We propose that BEC-ICOSL contributes to the firm adhesion of T cells to the barrier, promoting T cell transmigration into the CNS and eventually driving autoimmune neuroinflammation.

2023-11-03 | GSE221318 | GEO

Expression data from human umbilical vein endothelial cells (HUVECs) as a function of cell adhesion and VEGF exposure

Project description:Angiogenesis is tightly regulated by both soluble growth factors and cellular interactions with the extracellular matrix (ECM). While cell adhesion via integrins has been shown to be required for growth factor signaling and downstream angiogenesis, the effects of quantitative changes in cell adhesion and spreading against the ECM remain less clear. Examining changes in global gene expression in limited versus high adhesion contexts in human umbilical vein endothelial cells, we demonstrated a VEGF-induced upregulation of genes associated with vascular invasion and remodeling when cell adhesion was restricted, whereas cells on highly adhesive surfaces upregulated genes associated with a proliferative response.

2010-12-15 | GSE19098 | GEO

Human Cavernosal Endothelial Cell Phenotype

Project description:Purpose: To identify the molecular phenotype of endothelial cells (EC) isolated from the unique vasculature of the corpus cavernosum. Methods: Human EC derived from corpus cavernosum (HCCEC, n=5), coronary artery (HCAEC, n=4) and umbilical vein (HUVEC, n=3) were grown in culture and mRNA transcripts quantified by Affymetrix GeneChip microarrays. Genes differentially expressed across samples were partitioned around medoids to identify genes with highest expression in HCCEC. Several genes were verified by real-time PCR. The role of claudin 11 (CLDN11) in endothelial cell barrier function was examined by in vitro transendothelial electrical resistance assay. Results: Unsupervised hierarchical clustering of samples using all expressed genes yielded discrete groupings of EC lines according to their in vivo source of origin. 190 genes/transcripts were highly expressed only in cavernosal HCCEC. Gene Ontology classification indicated cavernosal enrichment in genes related to cell adhesion, extracellular matrix (ECM), pattern specification and organogenesis. KEGG pathway analysis showed high expression of gene relating to ECM-receptor interaction, focal adhesions, and cytokine-cytokine receptor interaction. Real-time PCR confirmed expression differences in cadherins 2 and 11, CLDN11, desmoplakin and versican. CLDN11, a component of tight junctions not previously described in ECs, was highly expressed only in HCCEC and its knockdown by siRNA significantly reduced transendothelial electrical resistance in HCCEC. Conclusions: HCCECs displayed expression of transcripts encoding matrix and adhesion proteins that regulate structural and functional characteristics of blood vessels. High expression of the tight junction protein CLDN11 is novel in endothelial cells and contributes to barrier function of cultured HCCEC. Keywords: penis, tight junctions, microarray, gene ontology, cell type comparison

2009-09-28 | GSE10804 | GEO

EPB41L5 controls podocyte extracellular matrix assembly by promoting integrin adhesome reinforcement - CDM dataset

Project description:The integrity of the kidney filtration barrier essentially relies on the balanced interplay of podocytes, endothelial cells and the glomerular basement membrane. Dysfunction in any of these components results in proteinuria and can progress to chronic kidney disease. While the relevance of cell-matrix interactions for podocytes is well established, it is only incompletely understood whether and how adhesion receptors reciprocally influence the basement membrane and maintain glomerular function. Here, we show by analysis of in vitro and in vivo models that a loss of the podocyte specific FERM-domain protein EPB41L5 results in impaired extracellular matrix integrity and stability. Employing quantitative proteomics analysis of the secretome, matrisome and integrin adhesome revealed that EPB41L5 promotes mechanosensitive properties of podocyte integrin complexes by recruitment of PDLIM5/ACTN4. Consecutively, EPB41L5 knockout podocytes showed insufficient reinforcement of integrin adhesion sites, which translated into impaired ECM assembly. These observations build the framework for a model where EPB41L5 as a cell type specific regulator of the podocyte adhesome controls a localized adaptive module in order to prevent podocyte detachment and ensures GBM integrity.

2021-01-26 | MSV000086766 | MassIVE

EPB41L5 controls podocyte extracellular matrix assembly by promoting integrin adhesome reinforcement - CCM dataset

2021-01-26 | MSV000086767 | MassIVE

Wnt5A signaling in human coronary artery endothelial cells

Project description:Inflammatory Wnt5A signalling in human macrophages was found to be critically involved in severe systemic inflammatory response. However, the targets of Wnt5A in endothelial cells and downstream mechanisms by which Wnt5A might induce endothelial inflammation still remain unclear. We show that Wnt5A principally regulate genes involved endothelial cytoskeleton rearrangements and impairs the barrier function of cultured endothelial monolayer causing hyper permeability. We further prove that Wnt5A neither affects the expression of adhesion molecules nor induces cytokine storm in endothelial cells. These findings suggest that Wnt5A, secreted by activated macrophages during septic inflammation, paracrinically act on the endothelial wall, causing endothelial barrier breakdown and subsequent vascular leakage in sepsis.

2016-10-03 | GSE62281 | GEO

TAp73 is a trophic factor essential for sperm cell adhesion and maturation in testis

Project description:A core evolutionary function of the p53 family is to protect the genomic integrity of gametes. However, the role of p73 in the male germline is unknown. Here we uncover that TAp73 unexpectedly functions as adhesion and maturation factor of the seminiferous epithelium orchestrating spermiogenesis. TAp73KO and p73KO mice, but not M-NM-^TNp73KO mice, display a M-bM-^@M-^Xnear-empty seminiferous tubuleM-bM-^@M-^Y phenotype due to massive premature loss of immature germ cells. Its cellular basis are defective cell-cell adhesions of developing germ cells to Sertoli nurse cells, with secondary degeneration of Sertoli cells including the blood-testis-barrier, thereby disrupting the adhesive integrity and maturation of the germ epithelium. At the molecular level, TAp73, produced in germ cells, controls a coordinated transcriptional program of adhesion- and migration-related proteins including peptidase inhibitors, proteases, receptors and integrins required for germ-Sertoli cell adhesion and dynamic junctional restructuring. Thus, the testis emerges as unique organ with strict division of labor among all family members: p63 and p53 safeguard germline fidelity, while TAp73 ensures fertility by enabling sperm maturation. 3 mice each for control wildtype and TAp73 knockout mice.

2013-12-31 | E-GEOD-46034 | biostudies-arrayexpress

TAp73 is essential for germ cell adhesion and maturation in testis

2014-03-07 | E-GEOD-52124 | biostudies-arrayexpress

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