Transforming growth factor-β2 promotes Snail-mediated endothelial–mesenchymal transition through convergence of Smad-dependent and Smad-independent signalling

Medici, Damian; Potenta, Scott; Kalluri, Raghu

doi:10.1042/bj20101500

Cited by 275 publications

(274 citation statements)

References 33 publications

(33 reference statements)

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“…These data indicate that active endothelial TGFβ signaling through ALK5 and the Smad2 and Smad3 transcription factors is associated with EndMT and confirms previous data reported by us and others (Kokudo et al, 2008;Krenning et al, 2008;Moonen et al, 2010;Medici et al, 2010Medici et al, , 2011Yoshida et al, 2012).…”

Section: Tgfβ1 Induces Endothelial-mesenchymal Transition In An Alk5-supporting

confidence: 81%

FGF2 inhibits endothelial–mesenchymal transition through microRNA-20a-mediated repression of canonical TGF-β signaling

Correia

Moonen

Brinker

et al. 2016

Journal of Cell Science

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Endothelial-to-mesenchymal transition (EndMT) is characterized by the loss of endothelial cell markers and functions, and coincides with de novo expression of mesenchymal markers. EndMT is induced by TGFβ1 and changes endothelial microRNA expression. We found that miR-20a is decreased during EndMT, and that ectopic expression of miR-20a inhibits EndMT induction. TGFβ1 induces cellular hypertrophy in human umbilical vein endothelial cells and abrogates VE-cadherin expression, reduces endothelial sprouting capacity and induces the expression of the mesenchymal marker SM22α (also known as TAGLN). We identified ALK5 (also known as TGFBR1), TGFBR2 and SARA (also known as ZFYVE9) as direct miR-20a targets. Expression of miR-20a mimics abrogate the endothelial responsiveness to TGFβ1, by decreasing ALK5, TGFBR2 and SARA, and inhibit EndMT, as indicated by the maintenance of VE-cadherin expression, the ability of the cells to sprout and the absence of SM22α expression. FGF2 increases miR-20a expression and inhibits EndMT in TGFβ1-stimulated endothelial cells. In summary, FGF2 controls endothelial TGFβ1 signaling by regulating ALK5, TGFBR2 and SARA expression through miR-20a. Loss of FGF2 signaling combined with a TGFβ1 challenge reduces miR-20a levels and increases endothelial responsiveness to TGFβ1 through elevated receptor complex levels and activation of Smad2 and Smad3, which culminates in EndMT.

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Section: Tgfβ1 Induces Endothelial-mesenchymal Transition In An Alk5-supporting

confidence: 81%

FGF2 inhibits endothelial–mesenchymal transition through microRNA-20a-mediated repression of canonical TGF-β signaling

Correia

Moonen

Brinker

et al. 2016

Journal of Cell Science

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“…The development of EndMT is abolished by use of a p38 MAPK inhibitor. EndMT induction via the overexpression of HD3-␣ or by direct stimulation with cytokines is decreased in the presence of a p38 MAPK inhibitor, suggesting that p38 MAPK is involved in EndMT (14,28). Additionally, it has been reported that p38 MAPK activation plays an important role in TGF-␤ intracellular signaling, promoting fibrotic actions (21,29).…”

Section: Discussionmentioning

confidence: 95%

Endotoxin-Induced Endothelial Fibrosis Is Dependent on Expression of Transforming Growth Factors β1 and β2

et al. 2014

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f During endotoxemia-induced inflammatory disease, bacterial endotoxins circulate in the bloodstream and interact with endothelial cells (ECs), inducing dysfunction of the ECs. We previously reported that endotoxins induce the conversion of ECs into activated fibroblasts. Through endotoxin-induced endothelial fibrosis, ECs change their morphology and their protein expression pattern, thereby suppressing endothelial markers and upregulating fibrotic proteins. The most commonly used fibrotic inducers are transforming growth factor ␤1 (TGF-␤1) and TGF-␤2. However, whether TGF-␤1 and TGF-␤2 participate in endotoxin-induced endothelial fibrosis remains unknown. We have shown that the endotoxin-induced endothelial fibrosis process is dependent on the TGF-␤ receptor, ALK5, and the activation of Smad3, a protein that is activated by ALK5 activation, thus suggesting that endotoxin elicits TGF-␤ production to mediate endotoxin-induced endothelial fibrosis. Therefore, we investigated the dependence of endotoxin-induced endothelial fibrosis on the expression of TGF-␤1 and TGF-␤2. Endotoxin-treated ECs induced the expression and secretion of TGF-␤1 and TGF-␤2. TGF-␤1 and TGF-␤2 downregulation inhibited the endotoxininduced changes in the endothelial marker VE-cadherin and in the fibrotic proteins ␣-SMA and fibronectin. Thus, endotoxin induces the production of TGF-␤1 and TGF-␤2 as a mechanism to promote endotoxin-induced endothelial fibrosis. To the best of our knowledge, this is the first report showing that endotoxin induces endothelial fibrosis via TGF-␤ secretion, which represents an emerging source of vascular dysfunction. These findings contribute to understanding the molecular mechanism of endotoxin-induced endothelial fibrosis, which could be useful in the treatment of inflammatory diseases.

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“…(vi) Furthermore, we used RT-qPCR and protein detection by western blot to demonstrate that H 2 O 2 induces the expression and secretion of TGF-b1 and TGF-b2, and it has been clearly demonstrated that TGF-b1 and TGF-b2 induce the conversion of ECs into myofibroblasts. 19,34,35,40,41,85 expression by converting them from normal to pathological. This information will be useful in designing new and improved therapeutic strategies against oxidative stressmediated systemic inflammatory diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, proteins that constitute the extracellular matrix (ECM), including fibronectin (FN), collagen type I and III, and vimentin are increased. [19][20][21][22] TGF-b binds its plasma membrane receptor, activin receptor-like kinase 5 (ALK5), to activate it and subsequently elicit intracellular signaling. 23,24 Several proteins that are involved in TGF-b intracellular signaling include the canonical pathway of phosphorylation of the family of Smad proteins and non-canonical intracellular pathways, to perform the activation of nuclear factor-kappa B (NF-kB).…”

mentioning

confidence: 99%

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Montorfano

Becerra

Cerro

et al. 2014

Laboratory Investigation

119

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During the pathogenesis of systemic inflammation, reactive oxygen species (ROS) circulate in the bloodstream and interact with endothelial cells (ECs), increasing intracellular oxidative stress. Although endothelial dysfunction is crucial in the pathogenesis of systemic inflammation, little is known about the effects of oxidative stress on endothelial dysfunction. Oxidative stress induces several functions, including cellular transformation. A singular process of cell conversion is tendothelial-to-mesenchymal transition, in which ECs become myofibroblasts, thus losing their endothelial properties and gaining fibrotic behavior. However, the participation of oxidative stress as an inductor of conversion of ECs into myofibroblasts is not known. Thus, we studied the role played by oxidative stress in this conversion and investigated the underlying mechanism. Our results show that oxidative stress induces conversion of ECs into myofibroblasts through decreasing the levels of endothelial markers and increasing those of fibrotic and ECM proteins. The underlying mechanism depends on the ALK5/Smad3/NF-kB pathway. Oxidative stress induces the expression and secretion of TGF-b1 and TGF-b2 and p38 MAPK phosphorylation. Downregulation of TGF-b1 and TGF-b2 by siRNA technology abolished the H 2 O 2 -induced conversion. To our knowledge, this is the first report showing that oxidative stress is able to induce conversion of ECs into myofibroblasts via TGF-b secretion, emerging as a source for oxidative stress-based vascular dysfunction. Thus, oxidative stress emerges as a decisive factor in inducing conversion of ECs into myofibroblasts through a TGF-b-dependent mechanism, changing the ECs protein expression profile, and converting normal ECs into pathological ones. This information will be useful in designing new and improved therapeutic strategies against oxidative stress-mediated systemic inflammatory diseases.

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Transforming growth factor-β2 promotes Snail-mediated endothelial–mesenchymal transition through convergence of Smad-dependent and Smad-independent signalling

Cited by 275 publications

References 33 publications

FGF2 inhibits endothelial–mesenchymal transition through microRNA-20a-mediated repression of canonical TGF-β signaling

FGF2 inhibits endothelial–mesenchymal transition through microRNA-20a-mediated repression of canonical TGF-β signaling

Endotoxin-Induced Endothelial Fibrosis Is Dependent on Expression of Transforming Growth Factors β1 and β2

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

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