TGF-beta 1/Smad3 expression and its effects on carotid intimal hyperplasia

Lü, Ping; Wang, Songhao; Cai, Wenwei; Sheng, Jing

doi:10.2741/522

Cited by 4 publications

(13 citation statements)

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“…26 We (and others) have also demonstrated in vivo that following gene transfer of Smad3, TGF- β enhances SMC proliferation as well as IH, whereas reducing Smad3 inhibits IH. 2, 34, 35 …”

Section: Discussionmentioning

confidence: 99%

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TGF-β/Smad3 inhibit vascular smooth muscle cell apoptosis through an autocrine signaling mechanism involving VEGF-A

et al. 2014

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We have previously shown that in the presence of elevated Smad3, transforming growth factor-β (TGF-β) transforms from an inhibitor to a stimulant of vascular smooth muscle cell (SMC) proliferation and intimal hyperplasia (IH). Here we identify a novel mechanism through which TGF-β/Smad3 also exacerbates IH by inhibiting SMC apoptosis. We found that TGF-β treatment led to inhibition of apoptosis in rat SMCs following viral expression of Smad3. Conditioned media from these cells when applied to naive SMCs recapitulated this effect, suggesting an autocrine pathway through a secreted factor. Gene array of TGF-β/Smad3-treated cells revealed enhanced expression of vascular endothelial growth factor (VEGF), a known inhibitor of endothelial cell apoptosis. We then evaluated whether VEGF is the secreted mediator responsible for TGF-β/Smad3 inhibition of SMC apoptosis. In TGF-β/Smad3-treated cells, VEGF mRNA and protein as well as VEGF secretion were increased. Moreover, recombinant VEGF-A inhibited SMC apoptosis and a VEGF-A-neutralizing antibody reversed the inhibitory effect of conditioned media on SMC apoptosis. Stimulation of SMCs with TGF-β led to the formation of a complex of Smad3 and hypoxia-inducible factor-1α (HIF-1α) that in turn activated the VEGF-A promoter and transcription. In rat carotid arteries following arterial injury, Smad3 and VEGF-A expression were upregulated. Moreover, Smad3 gene transfer further enhanced VEGF expression as well as inhibited SMC apoptosis. Finally, blocking either the VEGF receptor or Smad3 signaling in injured carotid arteries abrogated the inhibitory effect of Smad3 on vascular SMC apoptosis. Taken together, our study reveals that following angioplasty, elevation of both TGF-β and Smad3 leads to SMC secretion of VEGF-A that functions as an autocrine inhibitor of SMC apoptosis. This novel pathway provides further insights into the role of TGF-β in the development of IH.

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“…26 We (and others) have also demonstrated in vivo that following gene transfer of Smad3, TGF- β enhances SMC proliferation as well as IH, whereas reducing Smad3 inhibits IH. 2, 34, 35 …”

Section: Discussionmentioning

confidence: 99%

“…We and others have already demonstrated that Smad3 has an independent stimulatory effect on IH. 2, 34 …”

Section: Discussionmentioning

confidence: 99%

TGF-β/Smad3 inhibit vascular smooth muscle cell apoptosis through an autocrine signaling mechanism involving VEGF-A

et al. 2014

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“…TGF-β1/Smad2/3 signaling is a critical regulator in the pathological process of intimal hyperplasia and inhibition of the TGF-β1/Smad2/3 signaling pathway may reduce VSMC proliferation and collagen deposition, thus attenuating intimal hyperplasia ( 15 – 17 ). Therefore, the present study investigated whether the reduced VSMC proliferation and collagen deposition were mediated via TGF-β1/Smad2/3 pathway.…”

Section: Resultsmentioning

confidence: 99%

“…TGF-β1/Smad2/3 signaling has a key role in intimal hyperplasia; therefore, inhibition of the TGF-β/Smad2/3 signaling pathway may reduce VSMCs proliferation and collagen deposition, thus attenuating intimal hyperplasia ( 15 – 17 ). It is of note that the present study determined that honokiol treatment downregulated the protein expression level of p-Smad2/3, whereas the level of TGF-β1 and total Smad2/3 remained constant.…”

Section: Discussionmentioning

confidence: 99%

“…It is of note that the present study determined that honokiol treatment downregulated the protein expression level of p-Smad2/3, whereas the level of TGF-β1 and total Smad2/3 remained constant. TGF-β receptors may phosphorylate Smad2/3 ( 17 ); therefore, the present study investigated the expression of TGF-βRI and TGF-βRII. The results revealed that TGF-βRI and TGF-βRII were not significantly altered in the honokiol-treatment group.…”

Section: Discussionmentioning

confidence: 99%

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Local honokiol application inhibits intimal thickening in rabbits following carotid artery balloon injury

et al. 2017

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Honokiol is a natural bioactive product with anti-tumor, anti-inflammatory, anti-oxidative, anti-angiogenic and neuroprotective properties. The present study aimed to investigate the effects of honokiol treatment on intimal thickening following vascular balloon injury. The current study determined that perivascular honokiol application reduced intimal thickening in rabbits 14 days after carotid artery injury, it may inhibit vascular smooth muscle cell (VSMCs) proliferation and reduce collagen deposition in local arteries. The findings of the presents study also suggested that honikiol may increase the mRNA expression levels of matrix metalloproteinase-1 (MMP-1), MMP-2 and MMP-9 and decrease tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA expression in the rabbit arteries. Additionally, perivascular honokiol application inhibited intimal thickening, possibly via inhibition of the phosphorylation of SMAD family member 2/3.

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Role of TGF-β1/Smad3 Signaling Pathway in Secretion of Type I and III Collagen by Vascular Smooth Muscle Cells of Rats Undergoing Balloon Injury

Lü

Wang

Cai

et al. 2012

Journal of Biomedicine and Biotechnology

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Antisense Smad3 adenoviral vectors were used to transfect vascular smooth muscle cells (VSMCs) from rats with balloon injury or infused into the rat balloon-catheter injured carotid arteries, and the role of TGF-β1/Smad3 signaling pathway in the secretion of type I and III collagen by VSMCs following balloon injury was investigated. Antisense Smad3 adenoviral vectors were used to transfect these VSMCs (antisense Smad3 group). A total 90 rats were randomly assigned into blank control group, experiment group, negative control group. In the in vitro study, the expression of type I and III collagen was markedly reduced in the antisense Smad3 group when compared with the control groups (P < 0.05). In the in vivo study, the expression of type I and III collagen was significantly lower than that in the negative control group at 3 days, 1 week and 2 weeks after injury (P < 0.05). At 2 weeks and 3 months after injury, the lumen area in the antisense Smad3 group was markedly increased but the intimal area dramatically reduced when compared with the negative control (P < 0.05). We conclude that transfection of VSMCs with antisense Smad3 can reduce the secretion of type I and III collagen which then inhibit intimal hyperplasia.

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TGF-beta 1/Smad3 expression and its effects on carotid intimal hyperplasia

Cited by 4 publications

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TGF-β/Smad3 inhibit vascular smooth muscle cell apoptosis through an autocrine signaling mechanism involving VEGF-A

TGF-β/Smad3 inhibit vascular smooth muscle cell apoptosis through an autocrine signaling mechanism involving VEGF-A

Local honokiol application inhibits intimal thickening in rabbits following carotid artery balloon injury

Role of TGF-β1/Smad3 Signaling Pathway in Secretion of Type I and III Collagen by Vascular Smooth Muscle Cells of Rats Undergoing Balloon Injury

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