Adenovirus-Mediated Gene Transfer of a Secreted Transforming Growth Factor-β Type II Receptor Inhibits Luminal Loss and Constrictive Remodeling After Coronary Angioplasty and Enhances Adventitial Collagen Deposition

Kingston, Paul A.; Sinha, Sanjay; David, Anne; Castro, María G.; Löwenstein, Pedro R.; Heagerty, Anthony M.

doi:10.1161/hc4601.099405

Cited by 77 publications

(84 citation statements)

References 48 publications

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“…Several studies using gene transfer techniques have shown that locally enhanced TGF-␤ signaling enables matrix-rich neointima to develop in uninjured normal arteries of rats (11, 12). 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).…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…95 Adenoviral soluble TβRII can also inhibit constrictive remodeling after coronary angioplasty in pigs. 96 Pulmonary fibrosis has been successfully treated using adenovirus expression of decorin in the airway. 86 Administration of TGF-β antibodies prevents skin and lung fibrosis in murine sclerodermatous graft-vs-host 16 CM&R 2003 : 1 (January) Flanders and Burmester disease.…”

Section: Antagonists Of Tgf-β For Disease Treatmentmentioning

confidence: 99%

“…80 In this regard administration of adenoviral vectors of TGF-β or TGF-β antagonists is being widely used in animal models. 13,77,81,95,96 The administration of active-vs.-latent TGF-β is also an important consideration. Active TGF-β has a much shorter half-life than the latent form, 108 and active TGF-β may result in more side effects, since it is not subject to the activation step which is tightly controlled in vivo.…”

Section: Therapeutic Applications: Problems and Perspectivesmentioning

confidence: 99%

Medical Applications of Transforming Growth Factor-

Flanders¹,

Burmester²

2003

Clinical Medicine & Research

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Transforming growth factor-β (TGF-β) proteins and their antagonists have entered clinical trials. These multi-functional regulators of cell growth and differentiation induce extracellular matrix proteins and suppress the immune system making TGF-βs useful in treatment of wounds with impaired healing, mucositis, fractures, ischemia-reperfusion injuries, and autoimmune disease. In diseases such as keloids, glomerulonephritis and pulmonary fibrosis, excessive expression of TGF-β has been implicated as being responsible for accumulation of detrimental scar tissue. In these conditions, agents that block TGF-β have prevented or reversed disease. Similarly, in carcinogenesis, blocking TGF-β activity may be valuable in stimulating an immune response towards metastasis. As these blocking agents receive approval, we will likely have new therapies for previously recalcitrant diseases.

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“…Generation of Ad5-lacZ and RAd36 has been described previously. 9,20,21 Ad5-PP-lacZ, Ad5-PMEP-lacZ and Ad5-PREP-lacZ were generated by homologous recombination in 293 cells. 22 Stocks were purified by CsCl gradient centrifugation and titered by serial dilution end point in HEK 293 cells.…”

Section: Generation Of Recombinant Adenovirusesmentioning

confidence: 99%

A novel combination of promoter and enhancers increases transgene expression in vascular smooth muscle cells in vitro and coronary arteries in vivo after adenovirus-mediated gene transfer

et al. 2003

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Recombinant adenoviruses are employed widely for vascular gene transfer. Vascular smooth muscle cells (SMCs) are a relatively poor target for transgene expression after adenovirus-mediated gene delivery, however, even when expression is regulated by powerful, constitutive viral promoters. The major immediate-early murine cytomegalovirus enhancer/promoter (MIEmCMV) elicits substantially greater transgene expression than the human cytomegalovirus promoter (MIEhCMV) in all cell types in which they have been compared. The Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) increases transgene expression in numerous cell lines, and fragments of the smooth muscle myosin heavy chain (SMMHC) promoter increase expression within SMC from heterologous promoters. We therefore, compared the expression of b-galactosidase after adenovirus-mediated gene transfer of lacZ under the transcriptional regulation of a variety of combinations of the promoters and enhancers described, in vitro and in porcine coronary arteries. We demonstrate that inclusion of WPRE and a fragment of the rabbit SMMHC promoter along with MIEmCMV increases b-galactosidase expression 90-fold in SMC in vitro and E40-fold in coronary arteries, compared with vectors in which expression is regulated by MIEhCMV alone. Expression cassette modification represents a simple method of improving adenovirus-mediated vascular gene transfer efficiency and has important implications for the development of efficient cardiovascular gene therapy strategies.

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Adenovirus-Mediated Gene Transfer of a Secreted Transforming Growth Factor-β Type II Receptor Inhibits Luminal Loss and Constrictive Remodeling After Coronary Angioplasty and Enhances Adventitial Collagen Deposition

Cited by 77 publications

References 48 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

Medical Applications of Transforming Growth Factor-

A novel combination of promoter and enhancers increases transgene expression in vascular smooth muscle cells in vitro and coronary arteries in vivo after adenovirus-mediated gene transfer

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