Paracrine secretion of transforming growth factor-β1 in aneurysm healing and stabilization with endovascular smooth muscle cell therapy1 1Competition of interest: none.

Losy, Franck; Dai, Jianping; Pages, C.; Ginat, Maryvonne; Muscatelli-Groux, Béatrice; Guinault, Anne-Marie; Rousselle, Elodie; Smedile, Gianluca; Loisance, D; Becquemin, Jean‐Pierre; Allaire, Éric

doi:10.1016/s0741-5214(02)75336-6

Cited by 41 publications

(26 citation statements)

References 45 publications

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“…A previous endovascular vascular smooth muscle cell seeding experiment in rats showed that stabilization of the diameter of expanding experimental AAAs was associated with increased expression and paracrine secretion of TGF-β1 within the aorta, supporting its ability to promote healing of AAAs. 33 These reports further support our observations of the protective role of TGF-β1 in AAA pathogenesis. Leucine-serine-lysine-leucine (LSKL) peptide attenuates transforming growth factor-beta 1 (TGF-β1) activity and Smad signaling in angiotensin II (AngII)-infused ApoE −/− mice.…”

Section: Discussionsupporting

confidence: 87%

A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

Krishna

Seto

Jose

et al. 2015

ATVB

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This activation was observed to be dependent on the interaction between a specific TSP-1 sequence (lysine-argininephenylalanine-lysine; KRFK) and a conserved sequence (leucine-serine-lysine-leucine [LSKL]) near the amino terminus in the latency-associated peptide.14 The lysine--arginine-phenylalanine-lysine sequence interacts with the © 2014 American Heart Association, Inc.Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.114.304732Objective-Interaction of the activating sequence in thrombospondin-1 (TSP-1) with the conserved sequence (leucine-serinelysine-leucine [LSKL]) in the latency-associated peptide region of latent transforming growth factor (TGF)-β complex is important in regulating TGF-β1 activity. We aimed to assess the effect of blocking peptide LSKL on the progression of pre-established abdominal aortic aneurysm in angiotensin II-infused apolipoprotein E-deficient (ApoE −/− ) mice. Approach and Results-Abdominal aortic aneurysm was established in 3-month-old male ApoE −/− mice with subcutaneous infusion of angiotensin II for 28 days. After this, mice received LSKL peptide or control SLLK (serine-leucine-leucinelysine) peptide (4 mg/kg) via daily intraperitoneal injection for an additional 2 weeks. Administration of LSKL peptide promoted larger suprarenal aortic diameter, as determined by ultrasound and morphometric analysis, and stimulated more severe atherosclerosis within the aortic arch. In addition, mice receiving LSKL peptide exhibited elevated circulating proinflammatory cytokine levels and greater inflammatory cells within the suprarenal aorta compared with controls. Mice receiving LSKL peptide showed low plasma TGF-β1 activity and low levels of aortic tissue phosphorylated to total Smad2/3. Aortic gene expression of TGF-β receptor 1 (TGFBRI) and receptor 2 (TGFBRII), but not TGF-β1 and thrombospondin-1, were lower in mice receiving LSKL peptide than controls. LSKL peptide administration was associated with greater aortic elastin fragmentation and lower expression and activity of the TGF-β1-target gene lysyl oxidase like 1 (LOXL1). LSKL sequence to displace the latency-associated peptide and make the TGF-β1 accessible to its receptors, TGFBR I and II. 15 Previous studies have indicated that the conserved sequence (LSKL) is required for activation of TGF-β1 and that mimetic peptides of the sequence act as selective antagonists of TSP-1-mediated TGF-β1 activation in vitro and in vivo. [16][17][18] Previous reports suggest that LSKL peptide-mediated attenuation of TGF-β1 activation can prevent the progression of cardiac, hepatic, and renal interstitial fibrosis. 15,17,19 Complete deficiency of TGF-β1 pathway proteins has marked pathological effects, leading to in utero death. Conclusions-Attenuation 20,21Because TSP-1 provides only one of the means by which TGF-β1 is activated, targeting this protein could have clinical relevance as a less severe strategy with potential to be applied to patients. [22][23][24][25] We are aware of no previous studies whi...

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Section: Discussionsupporting

confidence: 87%

A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

Krishna

Seto

Jose

et al. 2015

ATVB

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“…37 We have shown previously that endovascular seeding of VSMCs stabilized the diameter of expanding experimental AAAs, supporting the concept that correction of the quantitative VSMC defect allows functional healing of AAAs. 14,38 Accumulation of VSMCs is elicited in normal and injured vessel wall by TGF-␤1 overexpression. 20,21 In the present study, overexpression of active TGF-␤1 resulted in the development of a VSMC-rich intimal thickening, which tended to replace the luminal thrombus and likely participated in wall strengthening because of its dense collagen and elastic fiber networks.…”

Section: Reconstruction Of the Artery Wallmentioning

confidence: 99%

Overexpression of Transforming Growth Factor-β1 Stabilizes Already-Formed Aortic Aneurysms

et al. 2005

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Background-The cell response to transforming growth factor-␤1 (TGF-␤1), a multipotent cytokine with healing potential, varies according to tissue context. We have evaluated the ability of TGF-␤1 overexpression by endovascular gene therapy to stabilize abdominal aortic aneurysms (AAAs) already injured by inflammation and proteolysis. Methods and Results-Active TGF-␤1 overexpression was obtained in already-developed experimental AAAs in rats after endovascular delivery of an adenoviral construct encoding for a mutated form of active simian TGF-␤1 and in an explant model using human atherosclerotic AAA fragments incubated with recombinant active TGF-␤1. Transient exogenous TGF-␤1 overexpression by endovascular gene delivery was followed by induction of endogenous rat TGF-␤1. Overexpression of active TGF-␤1 in experimental AAAs was associated with diameter stabilization, preservation of medial elastin, decreased infiltration of monocyte-macrophages and T lymphocytes, and a decrease in matrix metalloproteinase-2 and -9, which was also observed in the explant model, in both thrombus and wall. In parallel with downregulation of the destructive process, active TGF-␤1 overexpression triggered endoluminal reconstruction, replacing the thrombus by a vascular smooth muscle cell-, collagen-, and elastin-rich intima. Conclusions-Local TGF-␤1 self-induction after transient exogenous overexpression reprograms dilated aortas altered by inflammation and proteolysis and restores their ability to withstand arterial pressure without further dilation. This first demonstration of stabilization of expanding AAAs by delivery of a single multipotent self-promoting gene supports the view that endovascular gene therapy should be considered for treatment of aneurysms.

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“…69 TGF-␤ 1 may stabilize experimental aneurysms. 70 TGF-␤ 1 also inhibits proteolysis and endothelial cell migration. 71,72 Thus, TGF-␤ 1 could be locally expressed to inhibit recanalization and favor neointima formation at the neck of treated aneurysms.…”

Section: Candidate Genes To Improve Results Of Endovascular Treatmentmentioning

confidence: 99%

Gene Therapy and Endovascular Treatment of Intracranial Aneurysms

Ribourtout

Raymond

2004

Stroke

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Background-Endovascular treatment of intracranial aneurysms is safe and effective but too often is followed by recurrences. Gene therapy may improve healing after embolization, and endovascular approaches may offer future in situ delivery systems designed to prevent aneurysm rupture. Summary of Review-Advances in coil technology have focused on coating strategies designed to modify the biological reaction to the embolic agent. Gene therapy in cardiovascular applications is limited by low efficiency and transient gene expression. Current advances include the potential use of circulating progenitor cells for ex vivo genetic manipulations followed by in vivo delivery. Direct gene transfer may also be enhanced in situ by coils carrying antibody-tethered adenovirus or through the use of cell-specific or radiation-inducible promoters. Candidate genes that may be of value in promoting healing after endovascular treatment include growth factors and metalloproteinase inhibitors. A better understanding of the biology of aneurysm is necessary to conceive strategies designed to control the development of these lesions before their rupture. Conclusions-Many

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Paracrine secretion of transforming growth factor-β1 in aneurysm healing and stabilization with endovascular smooth muscle cell therapy1 1Competition of interest: none.

Abstract: Healing and stabilization of aneurysms with endovascular cell therapy is associated with a specific pattern of gene expression, resulting in paracrine secretion of TGF-beta(1). Our study provides insight into the molecular mechanisms of arterial aneurysm healing and stabilization.

Cited by 41 publications

References 45 publications

A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

Overexpression of Transforming Growth Factor-β1 Stabilizes Already-Formed Aortic Aneurysms

Gene Therapy and Endovascular Treatment of Intracranial Aneurysms

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