Established neointimal hyperplasia in vein grafts expands via TGF-β-mediated progressive fibrosis

Jiang, Zhihua; Tao, Ming; O’Malley, Kerri; Wang, Danlu; Ozaki, C. Keith; Berceli, Scott A.

doi:10.1152/ajpheart.00268.2009

Cited by 52 publications

(51 citation statements)

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“…CTGF gene expression is upregulated in pulmonary artery smooth muscle cells (PASMC) in monocrotaline-induced pulmonary hypertension (35). 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).…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…18–21 In rabbit VGs, TGF-β 1 upregulation persists for at least 6 months and is temporally associated with myofibroblast recruitment and matrix deposition that occur during vessel remodeling. 10,11,19 Our findings add to these data by demonstrating that TGF-β 1 is the dominant TGF-β isoform induced in VGs, that the primary stimulus for induction is vessel stretch rather than the direct effects of pressure, and that TGF-β 1 protein localized to the developing neointima early after implantation, concurrent with maximal suppression of endothelial TM expression, but predominated in the adventitia at later time points when endothelial TM expression returned. Although we found that systemic administration of a neutralizing anti-TGF-β antibody effectively prevented the downregulation of TM expression in the VG endothelium, we did not observe any effects on VG remodeling, especially neointima formation.…”

Section: Discussionmentioning

confidence: 52%

“…10,11 To determine if antibody-mediated TGF-β inhibition would alter VG remodeling, rabbits were intravenously administered 10 mg/kg of either the anti-TGF-β 1D11 or the13C4 control antibody biweekly beginning prior to VG implantation and continuing for 6 weeks until graft harvest. Despite having beneficial effects on endothelial thromboresistance, administration of the 1D11 antibody had no discernable effects on VG remodeling, including neointima formation (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of transforming growth factor-β restores endothelial thromboresistance in vein grafts

Kapur

Bian²,

Lin³

et al. 2011

Journal of Vascular Surgery

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Background Thrombosis is a major cause of the early failure of vein grafts (VGs) implanted during peripheral and coronary arterial bypass surgeries. Endothelial expression of thrombomodulin (TM), a key constituent of the protein C anticoagulant pathway, is markedly suppressed in VG after implantation and contributes to local thrombus formation. While stretch-induced paracrine release of transforming growth factor-β (TGF-β) is known to negatively regulate TM expression in heart tissue, its role in regulating TM expression in VGs remains unknown. Methods Changes in relative mRNA expression of major TGF-β isoforms were measured by qPCR in cultured human saphenous vein smooth muscle cells (HSVSMC) subjected to cyclic stretch. To determine the effects of paracrine release of TGF-β on endothelial TM mRNA expression, human saphenous vein endothelial cells (HSVEC) were co-cultured with stretched HSVSMC in the presence of 1D11, a pan-neutralizing TGF-β antibody, or 13C4, an isotype-control antibody. Groups of rabbits were then administered 1D11 or 13C4 and underwent interpositional grafting of jugular vein segments into the carotid circulation. The effect of TGF-β inhibition on TM gene expression was measured by qPCR, protein C activating capacity and local thrombus formation were measured by in situ chromogenic substrate assays, and VG remodeling was assessed by digital morphometry. Results Cyclic stretch induced TGF-β1 expression in HSVSMC by 1.9±0.2-fold, P<.001 without significant chang in the expressions of TGF-β2 and TGF-β3. Paracrine release of TGF-β1 by stretched HSVSMC inhibited TM expression in stationary HSVEC placed in co-culture by 57±12%, P=.03, an effect that was abolished in the presence of 1D11. Similarly, TGF-β1 was the predominant isoform induced in rabbit VGs 7 days after implantation (3.5±0.4-fold induction, P<.001). TGF-β1 protein expression localized predominantly to the developing neointima and coincided with marked suppression of endothelial TM expression (16±2% of vein controls, P<.03), a reduction in situ APC-generating capacity (53±9% of vein controls, P=.001) and increased local thrombus formation (3.7±0.8-fold increase over vein controls, P<.01). External stenting of VGs to limit vessel distension significantly reduced TGF-β1 induction and TM downregulation. Systemic administration of 1D11 also effectively prevented TM downregulation, preserved activated protein C-generating capacity and reduced local thrombus in rabbit VGs without observable effect on neointima formation and other morphometric parameters 6 weeks after implantation. Conclusion TM downregulation in VGs is mediated by paracrine release of TGF-β1 caused by pressure-induced vessel stretch. Systemic administration of an anti-TGF-β antibody effectively prevented TM downregulation and preserved local thromboresistance without negative effect on VG remodeling.

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“…TGF- β is a potent stimulator of extracellular matrix deposition during early stages of vein graft adaptation; enhanced TGF- β signaling promotes progressive fibrotic neointimal hyperplasia expansion (Jiang et al, 2009). TGF- β signaling is also a principal pathway regulating endothelial-mesenchymal transition, an important component of vein graft remodeling in mice and possibly humans (Cooley et al, 2014).…”

Section: Ephb4 and Ephrinb2-associated Signalingmentioning

confidence: 99%

Membrane‐mediated regulation of vascular identity

Hashimoto

Foster

Santana

et al. 2016

Birth Defects Research Pt C

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Vascular diseases span diverse pathology, but frequently arise from aberrant signaling attributed to specific membrane-associated molecules, particularly the Eph-ephrin family. Originally recognized as markers of embryonic vessel identity, Eph receptors and their membrane-associated ligands, ephrins, are now known to have a range of vital functions in vascular physiology. Interactions of Ephs with ephrins at cell-to-cell interfaces promote a variety of cellular responses such as repulsion, adhesion, attraction, and migration, and frequently occur during organ development, including vessel formation. Elaborate coordination of Eph-and ephrin-related signaling among different cell populations is required for proper formation of the embryonic vessel network. There is growing evidence supporting the idea that Eph and ephrin proteins also have postnatal interactions with a number of other membraneassociated signal transduction pathways, coordinating translation of environmental signals into cells. This article provides an overview of membrane-bound signaling mechanisms that define vascular identity in both the embryo and the adult, focusing on Eph-and ephrin-related signaling. We also discuss the role and clinical significance of this signaling system in normal organ development, neoplasms, and vascular pathologies.

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Established neointimal hyperplasia in vein grafts expands via TGF-β-mediated progressive fibrosis

Cited by 52 publications

References 51 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

Inhibition of transforming growth factor-β restores endothelial thromboresistance in vein grafts

Membrane‐mediated regulation of vascular identity

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