Arterial gene transfer of the TGF-β signalling protein Smad3 induces adaptive remodelling following angioplasty: a role for CTGF

Kundi, Rishi; Hollenbeck, Scott T.; Yamanouchi, Dai; Herman, Brad C.; Edlin, Rachel S.; Ryer, Evan J.; Wang, Chunjie; Tsai, Shirling; Liu, Bo; Kent, K. Craig

doi:10.1093/cvr/cvp220

Cited by 56 publications

(83 citation statements)

References 42 publications

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“…TGF-␤/CTGF signaling promotes progressive neointimal hyperplasia in vein grafts (27). Furthermore, CTGF is the downstream mediator of TGF-␤-induced adventitial remodeling in carotid angioplasty (32). This study provides for the first time the direct evidence that epithelial overexpression of CTGF causes excessive pulmonary vascular remodeling in the developing lung.…”

Section: Discussionmentioning

confidence: 67%

CTGF disrupts alveolarization and induces pulmonary hypertension in neonatal mice: implication in the pathogenesis of severe bronchopulmonary dysplasia

Chen

Rong

Platteau

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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S. CTGF disrupts alveolarization and induces pulmonary hypertension in neonatal mice: implication in the pathogenesis of severe bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 300: L330 -L340, 2011. First published January 14, 2011; doi:10.1152/ajplung.00270.2010.-The pathological hallmarks of bronchopulmonary dysplasia (BPD), one of the most common long-term pulmonary complications associated with preterm birth, include arrested alveolarization, abnormal vascular growth, and variable interstitial fibrosis. Severe BPD is often complicated by pulmonary hypertension characterized by excessive pulmonary vascular remodeling and right ventricular hypertrophy that significantly contributes to the mortality and morbidity of these infants. Connective tissue growth factor (CTGF) is a multifunctional protein that coordinates complex biological processes during tissue development and remodeling. We have previously shown that conditional overexpression of CTGF in airway epithelium under the control of the Clara cell secretory protein promoter results in BPD-like architecture in neonatal mice. In this study, we have generated a doxycycline-inducible double transgenic mouse model with overexpression of CTGF in alveolar type II epithelial (AT II) cells under the control of the surfactant protein C promoter. Overexpression of CTGF in neonatal mice caused dramatic macrophage and neutrophil infiltration in alveolar air spaces and perivascular regions. Overexpression of CTGF also significantly decreased alveolarization and vascular development. Furthermore, overexpression of CTGF induced pulmonary vascular remodeling and pulmonary hypertension. Most importantly, we have also demonstrated that these pathological changes are associated with activation of integrin-linked kinase (ILK)/glucose synthesis kinase-3␤ (GSK-3␤)/␤-catenin signaling. These data indicate that overexpression of CTGF in AT II cells results in lung pathology similar to those observed in infants with severe BPD and that ILK/GSK-3␤/␤-catenin signaling may play an important role in the pathogenesis of severe BPD.

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Section: Discussionmentioning

confidence: 67%

CTGF disrupts alveolarization and induces pulmonary hypertension in neonatal mice: implication in the pathogenesis of severe bronchopulmonary dysplasia

Chen

Rong

Platteau

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Endothelial cell-specific Fli1 knockout mice mimic vascular disintegrity of SSc which is characterized by reduced interaction between endothelial cells and PCs/vSMCs due to the activation of proangiogenic gene program [40]. Periadventitial administration of recombinant CTGF induces neointimal thickening, enlargement of an external elastic lamina area, adventitial collagen accumulation, adventitial myofibroblast transformation, and proliferation of vascular wall cells [92]. Given that SSc is a multifactorial disease including heterogeneous disease subsets, it is speculated that the simultaneous deficiency of KLF5 and Fli1 genes contributes to the development of a certain subset of SSc.…”

Section: Animal Models Of Ssc Vasculopathymentioning

confidence: 99%

Vasculopathy in scleroderma

2015

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Systemic sclerosis (SSc) is a multisystem connective tissue disorder featured by vascular injury and fibrosis of the skin and various internal organs with autoimmune background. Although the pathogenesis of SSc still remains elusive, it is generally accepted that initial vascular injury due to autoimmunity and/or environmental factors causes structural and functional abnormalities of vasculature which eventually result in the constitutive activation of fibroblasts in various organs. Structural alterations consist of destructive vasculopathy (loss of small vessels) and proliferative obliterative vasculopathy (occlusion of arterioles and small arteries with fibro-proliferative change) caused by impaired compensatory vasculogenesis and angiogenesis. Impaired function of SSc vasculature includes the altered expression of cell adhesion molecules predominantly inducing Th2 and Th17 cell infiltration, endothelial dysfunction primarily due to the low availability of nitric oxide, the activated endothelial-to-mesenchymal transition leading to fibro-proliferative vascular change and tissue fibrosis, and the impaired coagulation/fibrinolysis system promoting the formation of intravascular fibrin deposits. Recent new insights into the therapeutic mechanisms of intravenous cyclophosphamide pulse and bosentan and the establishment of a new SSc animal model (Klf5 (+/-);Fli1 (+/-) mice) provide us useful clues to further understand the development of vascular alterations characteristic of SSc. This article overviewed the present understanding of the pathogenesis of SSc vasculopathy.

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“…Hu et al have shown that TGF-β1 may contribute to the up-regulation of α-SMA via Smad3 in rat lung fibroblasts (30). Any adventitial effect of Smad3 overexpression was found to be indirect, mediated by infected medial or neointimal cells (31), but this research did not have a relevant control group to exclude other factors that up-regulated Smad3 overexpression directly in adventitia. in our study, we found that after direct induction by TGF-β1, Smad3 and pho-Smad3 were increased.…”

Section: Discussionmentioning

confidence: 81%

Smad2 and Smad3 as mediators of the response of adventitial fibroblasts induced by transforming growth factor β1

et al. 2011

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Abstract. Transforming growth factor β1 (TGF-β1) is a known pleiotropic growth factor in cell proliferation, migration and phenotypic transition. Fibroblasts are considered the most reactive in the vascular wall. We aimed to explore the effect and mechanism of TGF-β1 on aortal adventitial fibroblasts (AFs) induced by TGF-β1. aFs were cultured in vitro by tissue explants. after stimulation by TGF-β1 and treatment with small interfering rna (sirna)-Smad2 and sirna-Smad3, MTT and the transwell chamber techniques were used for assessing aF proliferation and migration. The expression of phospho (pho)-Smad2, pho-Smad3, Smad7, α-smooth muscle actin (SMa) and collagen i and iii were evaluated by Western blot analysis and real-time rT-Pcr. after stimulation by TGF-β1 for 24 h, the proliferation and migration of treated aFs were higher compared to those of untreated aFs, as was the expression of Smad2, Smad3, phoSmad2, pho-Smad3, SMa and collagen i and iii (P<0.05), but not Smad7 (P>0.05). Knockdown of Smad2 and Smad3 inhibited proliferation and migration of aFs and downregulated the expression of SMa and collagen i and iii (P<0.05). TGF-β1 plays a key role in remodeling processes by contributing to the proliferation, migration and phenotypic modulation of aFs and collagen composition. The mechanism may be related to both the Smad2 and Smad3 signaling pathways.

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Arterial gene transfer of the TGF-β signalling protein Smad3 induces adaptive remodelling following angioplasty: a role for CTGF

Abstract: Medial gene transfer of Smad3 promotes adaptive remodelling by indirectly influencing the behaviour of adventitial fibroblasts. This arterial cell-cell communication is likely to be mediated by Smad3-dependent production of CTGF.

Cited by 56 publications

References 42 publications

CTGF disrupts alveolarization and induces pulmonary hypertension in neonatal mice: implication in the pathogenesis of severe bronchopulmonary dysplasia

CTGF disrupts alveolarization and induces pulmonary hypertension in neonatal mice: implication in the pathogenesis of severe bronchopulmonary dysplasia

Vasculopathy in scleroderma

Smad2 and Smad3 as mediators of the response of adventitial fibroblasts induced by transforming growth factor β1

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