228 research outputs found
Association of gene variants in the TGF-beta signalling pathways with invasive breast cancer risk
The functional relationship between transglutaminase 2 and transforming growth factor Ξ²1 in the regulation of angiogenesis and endothelial-mesenchymal transition
The importance of transglutaminase 2 (TG2) in angiogenesis has been highlighted in recent studies, but other roles of this multi-functional enzyme in endothelial cell (EC) function still remains to be fully elucidated. We previously showed that the extracellular TG2 is involved in maintaining tubule formation in ECs by a mechanism involving matrix-bound vascular endothelial growth factor (VEGF) signalling. Here, by using the ECs and fibroblast co-culture and ECs 3D culture models, we demonstrate a further role for TG2 in both endothelial tubule formation and in tubule loss, which involves its role in the regulation of transforming growth factor Ξ²1 (TGFΞ²1) and Smad signalling. We demonstrate that inhibition of tubule formation by TG2 inhibitors can be restored by add-back of exogenous TGFΞ²1 at pg/ml levels and show that TG2 -/- mouse ECs are unable to form tubules in 3D culture and display negligible Smad signalling compared to wild-type cells. Loss of tubule formation in the TG2 -/- ECs can be reconstituted by transduction with TG2. We demonstrate that extracellular TG2 also has an important role in TGFΞ²1-induced transition of ECs into myofibroblast-like cells (endothelial-mesenchymal transition), resulting in loss of EC tubules and tubule formation. Our data also indicate that TG2 may have a role in regulating TGFΞ² signalling through entrapment of active TGFΞ²1 into the extracellular matrix. In conclusion, our work demonstrates that TG2 has multi-functional roles in ECs where its ability to fine-tune of TGFΞ²1 signalling means it can be involved in both endothelial tubule formation and tubule rarefaction
Dynamic regulation of canonical TGF beta signalling by endothelial transcription factor ERG protects from liver fibrogenesis
The role of the endothelium in protecting from chronic liver disease and TGFΞ²-mediated
fibrosis remains unclear. Here we describe how the endothelial transcription factor
ETS-related gene (ERG) promotes liver homoeostasis by controlling canonical TGFΞ²-SMAD
signalling, driving the SMAD1 pathway while repressing SMAD3 activity. Molecular analysis
shows that ERG binds to SMAD3, restricting its access to DNA. Ablation of ERG expression
results in endothelial-to-mesenchymal transition (EndMT) and spontaneous liver
fibrogenesis in EC-specific constitutive hemi-deficient (ErgcEC-Het) and inducible homozygous
deficient mice (ErgiEC-KO), in a SMAD3-dependent manner. Acute administration of the
TNF-Ξ± inhibitor etanercept inhibits carbon tetrachloride (CCL4)-induced fibrogenesis in an
ERG-dependent manner in mice. Decreased ERG expression also correlates with EndMT in
tissues from patients with end-stage liver fibrosis. These studies identify a pathogenic
mechanism where loss of ERG causes endothelial-dependent liver fibrogenesis via regulation
of SMAD2/3. Moreover, ERG represents a promising candidate biomarker for assessing
EndMT in liver disease
BAMBI Regulates Angiogenesis and Endothelial Homeostasis through Modulation of Alternative TGFΞ² Signaling
BACKGROUND: BAMBI is a type I TGFΞ² receptor antagonist, whose in vivo function remains unclear, as BAMBI(-/-) mice lack an obvious phenotype. METHODOLOGY/PRINCIPAL FINDINGS: Identifying BAMBI's functions requires identification of cell-specific expression of BAMBI. By immunohistology we found BAMBI expression restricted to endothelial cells and by electron microscopy BAMBI(-/-) mice showed prominent and swollen endothelial cells in myocardial and glomerular capillaries. In endothelial cells over-expression of BAMBI reduced, whereas knock-down enhanced capillary growth and migration in response to TGFΞ². In vivo angiogenesis was enhanced in matrigel implants and in glomerular hypertrophy after unilateral nephrectomy in BAMBI(-/-) compared to BAMBI(+/+) mice consistent with an endothelial phenotype for BAMBI(-/-) mice. BAMBI's mechanism of action in endothelial cells was examined by canonical and alternative TGFΞ² signaling in HUVEC with over-expression or knock-down of BAMBI. BAMBI knockdown enhanced basal and TGFΞ² stimulated SMAD1/5 and ERK1/2 phosphorylation, while over-expression prevented both. CONCLUSIONS/SIGNIFICANCE: Thus we provide a first description of a vascular phenotype for BAMBI(-/-) mice, and provide in vitro and in vivo evidence that BAMBI contributes to endothelial and vascular homeostasis. Further, we demonstrate that in endothelial cells BAMBI interferes with alternative TGFΞ² signaling, most likely through the ALK 1 receptor, which may explain the phenotype observed in BAMBI(-/-) mice. This newly described role for BAMBI in regulating endothelial function has potential implications for understanding and treating vascular disease and tumor neo-angiogenesis
Hippo pathway effectors control cardiac progenitor cell fate by acting as dynamic sensors of substrate mechanics and nanostructure
Stem cell responsiveness to extracellular matrix (ECM) composition and mechanical cues has been the subject of a number of investigations so far, yet the molecular mechanisms underlying stem cell mechano-biology still need full clarification. Here we demonstrate that the paralog proteins YAP and TAZ exert a crucial role in adult cardiac progenitor cell mechano-sensing and fate decision. Cardiac progenitors respond to dynamic modifications in substrate rigidity and nanopattern by promptly changing YAP/TAZ intracellular localization. We identify a novel activity of YAP and TAZ in the regulation of tubulogenesis in 3D environments and highlight a role for YAP/TAZ in cardiac progenitor proliferation and differentiation. Furthermore, we show that YAP/TAZ expression is triggered in the heart cells located at the infarct border zone. Our results suggest a fundamental role for the YAP/TAZ axis in the response of resident progenitor cells to the modifications in microenvironment nanostructure and mechanics, thereby contributing to the maintenance of myocardial homeostasis in the adult heart. These proteins are indicated as potential targets to control cardiac progenitor cell fate by materials design
Regulation of endothelial cell plasticity by TGF-Ξ²
Recent evidence has demonstrated that endothelial cells can have a remarkable plasticity. By a process called Endothelial-to-Mesenchymal Transition (EndMT) endothelial cells convert to a more mesenchymal cell type that can give rise to cells such as fibroblasts, but also bone cells. EndMT is essential during embryonic development and tissue regeneration. Interestingly, it also plays a role in pathological conditions like fibrosis of organs such as the heart and kidney. In addition, EndMT contributes to the generation of cancer associated fibroblasts that are known to influence the tumor-microenvironment favorable for the tumor cells. EndMT is a form of the more widely known and studied Epithelial-to-Mesenchymal Transition (EMT). Like EMT, EndMT can be induced by transforming growth factor (TGF)-Ξ². Indeed many studies have pointed to the important role of TGF-Ξ² receptor/Smad signaling and downstream targets, such as Snail transcriptional repressor in EndMT. By selective targeting of TGF-Ξ² receptor signaling pathological EndMT may be inhibited for the therapeutic benefit of patients with cancer and fibrosis
Age-dependent alteration of TGF-Ξ² signalling in osteoarthritis
Osteoarthritis (OA) is a disease of articular cartilage, with aging as the main risk factor. In OA, changes in chondrocytes lead to the autolytic destruction of cartilage. Transforming growth factor-Ξ² has recently been demonstrated to signal not only via activin receptor-like kinase 5 (ALK5)-induced Smad2/3 phosphorylation, but also via ALK1-induced Smad1/5/8 phosphorylation in articular cartilage. In aging cartilage and experimental OA, the ratio ALK1/ALK5 has been found to be increased, and the expression of ALK1 is correlated with matrix metalloproteinase-13 expression. The age-dependent shift towards Smad1/5/8 signalling might trigger the differentiation of articular chondrocytes with an autolytic phenotype
Regulation of oligodendrocyte progenitor cell maturation by PPARΞ΄: effects on bone morphogenetic proteins
In EAE (experimental autoimmune encephalomyelitis), agonists of PPARs (peroxisome proliferator-activated receptors) provide clinical benefit and reduce damage. In contrast with PPARΞ³, agonists of PPARΞ΄ are more effective when given at later stages of EAE and increase myelin gene expression, suggesting effects on OL (oligodendrocyte) maturation. In the present study we examined effects of the PPARΞ΄ agonist GW0742 on OPCs (OL progenitor cells), and tested whether the effects involve modulation of BMPs (bone morphogenetic proteins). We show that effects of GW0742 are mediated through PPARΞ΄ since no amelioration of EAE clinical scores was observed in PPARΞ΄-null mice. In OPCs derived from E13 mice (where E is embryonic day), GW0742, but not the PPARΞ³ agonist pioglitazone, increased the number of myelin-producing OLs. This was due to activation of PPARΞ΄ since process formation was reduced in PPARΞ΄-null compared with wild-type OPCs. In both OPCs and enriched astrocyte cultures, GW0742 increased noggin protein expression; however, noggin mRNA was only increased in astrocytes. In contrast, GW0742 reduced BMP2 and BMP4 mRNA levels in OPCs, with lesser effects in astrocytes. These findings demonstrate that PPARΞ΄ plays a role in OPC maturation, mediated, in part, by regulation of BMP and BMP antagonists
Endothelial Mesenchymal Transition: Comparative Analysis of Different Induction Methods
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