Expression of transforming growth factor-beta 1 is increased in human vascular restenosis lesions.

Nikol, Sigrid; Isner, Jeffrey M.; Pickering, J. Geoffrey; Kearney, Marianne; Lochard, Guy; Weir, Lawrence

doi:10.1172/jci116027

Cited by 366 publications

(192 citation statements)

References 56 publications

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“…In contrast, localized blockade of TGF-␤ signaling results in the inhibition of neointimal formation, accompanied by reduced extracellular matrix synthesis in a rat balloon-injury model (13,14). Of clinical relevance is the observation that the expression levels of TGF-␤ mRNA in restenotic lesions are higher than those in primary atherosclerotic lesions (15). These investigations indicate that TGF-␤ functions as a fibrogenic cytokine in a balloon-injury model, and apparently aggravates neointimal formation by promoting fibrosis.…”

Section: Discussionmentioning

confidence: 95%

Vasorin, a transforming growth factor β-binding protein expressed in vascular smooth muscle cells, modulates the arterial response to injury in vivo

Ikeda

Imai

Kumagai

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

120

142

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Growth factors, cell-surface receptors, adhesion molecules, and extracellular matrix proteins play critical roles in vascular pathophysiology by affecting growth, migration, differentiation, and survival of vascular cells. In a search for secreted and cell-surface molecules expressed in the cardiovascular system, by using a retrovirus-mediated signal sequence trap method, we isolated a cell-surface protein named vasorin. Vasorin is a typical type I membrane protein, containing tandem arrays of a characteristic leucine-rich repeat motif, an epidermal growth factor-like motif, and a fibronectin type III-like motif at the extracellular domain. Expression analyses demonstrated that vasorin is predominantly expressed in vascular smooth muscle cells, and that its expression is developmentally regulated. To clarify biological functions of vasorin, we searched for its binding partners and found that vasorin directly binds to transforming growth factor (TGF)-␤ and attenuates TGF-␤ signaling in vitro. Vasorin expression was downregulated during vessel repair after arterial injury, and reversal of vasorin down-regulation, by using adenovirus-mediated in vivo gene transfer, significantly diminished injury-induced vascular lesion formation, at least in part, by inhibiting TGF-␤ signaling in vivo. These results suggest that down-regulation of vasorin expression contributes to neointimal formation after vascular injury and that vasorin modulates cellular responses to pathological stimuli in the vessel wall. Thus, vasorin is a potential therapeutic target for vascular fibroproliferative disorders. V ascular smooth muscle cells (VSMCs), the major cell type in the vessel wall, show a spectrum of phenotypes, depending on environmental cues. Various injurious stimuli provoke the proliferation of differentiated medial VSMCs, which migrate to the intima and produce extracellular matrix proteins, resulting in the narrowing of the vascular lumen. These processes, called VSMC phenotypic modulation, play a key role in development of atherosclerotic diseases, such as postangioplasty restenosis, vein graft disease, and transplant vasculopathy. Whereas tremendous progress has been made in identifying growth factors and transcription factors that regulate the vascular response to injury, much information is lacking regarding cell-surface molecules that are involved in the pathogenesis of vascular fibroproliferative disorders. The signal sequence trap (SST) is a strategy to identify cDNAs containing signal sequence that encode secreted and type I membrane proteins (1, 2). We recently developed a refined SST system based on retrovirusmediated expression screening (SST-REX) (3). In a search for secreted and cell-surface molecules expressed in the cardiovascular system, by using SST-REX, we identified a TGF-␤ binding protein, vasorin. Vasorin is predominantly expressed in VSMCs and modulates the vascular response to injury, at least in part, by attenuating TGF-␤ signaling in vivo. Here, we describe the molecular and functional characteristics of...

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Section: Discussionmentioning

confidence: 95%

Vasorin, a transforming growth factor β-binding protein expressed in vascular smooth muscle cells, modulates the arterial response to injury in vivo

Ikeda

Imai

Kumagai

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

120

142

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“…TGFβ1 has been reported to express in vascular wall, including endothelial cells, vascular smooth muscle cells, monocytes/macrophages, regulatory T cells and myofibroblasts 16. Expression of TGFβ1 and receptors is increased in human atherosclerotic plaque lesion, especially in fibro‐proliferative regions, compared with non‐atherosclerotic regions 17, 18. TGFβ1 can stimulate endothelial migration, proliferation and angiogenesis at low concentrations, but inhibit these functions at higher concentrations, which associated with increased extracellular matrix 19.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐216a induces endothelial senescence and inflammation via Smad3/IκBα pathway

Yang

Chen

et al. 2018

J Cellular Molecular Medi

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Vascular endothelial senescence contributes to atherosclerosis and coronary artery disease (CAD), but the mechanisms are yet to be clarified. We identified that microRNA‐216a (miR‐216a) significantly increased in senescent endothelial cells. The replicative senescence model of human umbilical vein endothelial cells (HUVECs) was established to explore the role of miR‐216a in endothelial ageing and dysfunction. Luciferase assay indicated that Smad3 was a direct target of miR‐216a. Stable expression of miR‐216a induced a premature senescence‐like phenotype in HUVECs with an impairment in proliferation and migration and led to an increased adhesion to monocytes by inhibiting Smad3 expression and thereafter modulating the degradation of NF‐κB inhibitor alpha (IκBα) and activation of adhesion molecules. Conversely, inhibition of endogenous miR‐216a in senescent HUVECs rescued Smad3 and IκBα expression and inhibited monocytes attachment. Plasma miR‐216a was significantly higher in old CAD patients (>50 years) and associated with increased 31% risk for CAD (odds ratio 1.31, 95% confidence interval 1.03‐1.66; P = .03) compared with the matched healthy controls (>50 years). Taken together, our data suggested that miR‐216a promotes endothelial senescence and inflammation as an endogenous inhibitor of Smad3/IκBα pathway, which might serve as a novel target for ageing‐related atherosclerotic diseases.

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“…The observed induction of mitogen mRNA expression in cultured bovine vascular SMC, data which although not necessarily reflecting similar changes on the protein levels of the respective mitogens, are, however, very much consistent with in situ findings that transcripts for several growth factors and their receptors including PDGF-B, the [3-subunit of the PDGF receptor, and TGF-~I were increased in advanced atherosclerotic lesions. In contrast, growth-promoting molecules and their specific receptors are not expressed in SMC from the tunica media of normal arteries or in regions of the intima unaffected by atherosclerosis [28].…”

Section: Resultsmentioning

confidence: 94%

Mitogen crosstalk accompanying urokinase receptor expression in stimulated vascular smooth muscle cells

et al. 1996

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Thrombin and other mitogens regulate the expression of the urokinase-type plasminogen activator receptor (uPAR) protein and mRNA levels in bovine vascular smooth muscle cells (SMC). We investigated interactions between mitogens capable of increasing uPAR mRNA levels in SMC. Up-regulation of uPAR mRNA upon thrombin and basic fibroblast growth factor (bFGF) stimulation was preceded by a 2-3-fold transient increase in bFGF mRNA within 1 h. TGF-[~I did not result in a significant change in bFGF mRNA levels. Platelet-derived growth factor (PDGF) while substantially enhancing uPAR mRNA levels, diminished bFGF mRNA levels by 3-4-fold. Both thrombin and bFGF induced the message for bFGF-R 2-3-fold. Thrombin also provoked a 3-4-fold rise in TGF-[~I mRNA levels within 30 rain. In summary, on the mRNA level, we demonstrated both positive as well as negative feed-back mechanisms between different mitogens, among them bFGF revealing in addition to autoinduction also up-regulation of the transcript concentration of its own receptor. Thus, cooperation and possible amplification of mitogenic effects might be implicated in the fine-tuned regulation of uPAR mRNA in stimulated bovine aorta SMC.

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Expression of transforming growth factor-beta 1 is increased in human vascular restenosis lesions.

Cited by 366 publications

References 56 publications

Vasorin, a transforming growth factor β-binding protein expressed in vascular smooth muscle cells, modulates the arterial response to injury in vivo

Vasorin, a transforming growth factor β-binding protein expressed in vascular smooth muscle cells, modulates the arterial response to injury in vivo

MicroRNA‐216a induces endothelial senescence and inflammation via Smad3/IκBα pathway

Mitogen crosstalk accompanying urokinase receptor expression in stimulated vascular smooth muscle cells

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