Fibronectin Is an Important Regulator of Flow-Induced Vascular Remodeling

Chiang, Hou‐Yu; Korshunov, Vyacheslav A.; Serour, Andrew; Shi, Feng; Sottile, Jane

doi:10.1161/atvbaha.108.181081

Cited by 147 publications

(180 citation statements)

References 60 publications

(87 reference statements)

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“…We showed here that inhibition of β-catenin signaling downregulated cyclin D1 expression in CTGF transgenic lungs suggesting that cyclin D1 is one of the CTGF-β-catenin targets that may cause vascular smooth muscle cell proliferation in the neonatal lungs. Fibronectin, another β-catenin target gene, is not only a key component of vascular ECM but also an important regulator of pulmonary vascular remodeling and pulmonary arterial hypertension (36). We found that administration of ICG001 downregulated fibronectin gene expression and decreased fibronectin protein expression in peripheral pulmonary vessels in CTGF transgenic lungs.…”

Section: Discussionmentioning

confidence: 68%

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

et al. 2016

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Background: Bronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease of premature infants. Connective tissue growth factor (CTGF) plays an important role in tissue development and remodeling. We have previously shown that targeted overexpression of CTGF in alveolar type II epithelial cells results in BPD-like pathology and activates β-catenin in neonatal mice. Methods: Utilizing this transgenic mouse model and ICG001, a specific pharmacological inhibitor of β-catenin, we tested the hypothesis that β-catenin signaling mediates the effects of CTGF in the neonatal lung. Newborn CTGF mice and control littermates received ICG001 (10 mg/kg/dose) or placebo (dimethyl sulfoxide, equal volume) by daily i.p. injection from postnatal day 5 to 15. Alveolarization, vascular development, and pulmonary hypertension (PH) were analyzed. results: Administration of ICG001 significantly downregulated expression of cyclin D1, collagen 1a1, and fibronectin, which are the known target genes of β-catenin signaling in CTGF lungs. Inhibition of β-catenin signaling improved alveolar and vascular development and decreased pulmonary vascular remodeling. More importantly, the improved vascular development and vascular remodeling led to a decrease in PH. conclusion: β-Catenin signaling mediates the autocrine and paracrine effects of CTGF in the neonatal lung. Inhibition of CTGF-β-catenin signaling may provide a novel therapy for BPD. INTRODUCTIONBronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease of premature infants (1). Over the past four decades, the incidence of this disease has significantly increased as a result of improved survival of extremely-low-birthweight infants (2). The pathology of BPD is increasingly being recognized as a developmental arrest of the immature lung caused by injurious stimuli such as mechanical ventilation, oxygen exposure, and intrauterine or postnatal infections. Larger and simplified alveoli, decreased vascular growth, and variable interstitial fibrosis are the key pathological features observed in lungs of infants who died of BPD (1). The combination of decreased vascular growth and excessive pulmonary vascular remodeling leads to pulmonary hypertension (PH) which significantly contributes to the morbidity and mortality of these infants (3). Yet, the underlying cellular and molecular mechanisms are poorly defined, and there is no effective therapy.Connective tissue growth factor (CTGF) is a matricellular protein that plays an important role in tissue development and remodeling (4). Recent studies have highlighted the potential role of CTGF in BPD development and progression. The clinical association of CTGF with BPD is best established by studies demonstrating increased CTGF concentrations in bronchoalveolar lavage fluid from preterm infants developing BPD (5) and increased CTGF expression in lung tissues of infants who died of BPD (6). Multiple studies have examined the potential role of CTGF in experimental BPD and demonstrated that increased CTG...

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Section: Discussionmentioning

confidence: 68%

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

et al. 2016

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“…FN-null MFs were cultured with 10 mg/ml fibronectin overnight in the presence or absence of pUR4, a fibronectin polymerization inhibitor. Previous studies have shown that cells elaborate a robust fibronectin matrix in the presence of the control peptide, but that pUR4 drastically reduces the deposition of ECM fibronectin (Chiang et al, 2009;Tomasini-Johansson et al, 2001). As shown in Fig.…”

Section: Fibronectin Polymerization Regulates Endocytosis Of A5b1 Intmentioning

confidence: 62%

MT1-MMP regulates the turnover and endocytosis of extracellular matrix fibronectin

Shi

Sottile

2011

Journal of Cell Science

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109

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SummaryThe extracellular matrix (ECM) is dynamically remodeled by cells during development, normal tissue homeostasis and in a variety of disease processes. We previously showed that fibronectin is an important regulator of ECM remodeling. The deposition and/or polymerization of fibronectin into the ECM controls the deposition and stability of other ECM molecules. In addition, agents that inhibit fibronectin polymerization promote the turnover of fibronectin fibrils and enhance ECM fibronectin endocytosis and intracellular degradation. Endocytosis of ECM fibronectin is regulated by b1 integrins, including a5b1 integrin. We have examined the role of extracellular proteases in regulating ECM fibronectin turnover. Our data show that membrane type matrix metalloproteinase 1 (MT1-MMP; also known as MMP14) is a crucial regulator of fibronectin turnover. Cells lacking MT1-MMP show reduced turnover and endocytosis of ECM fibronectin. MT1-MMP regulates ECM fibronectin remodeling by promoting extracellular cleavage of fibronectin and by regulating a5b1-integrin endocytosis. Our data also show that fibronectin polymerization stabilizes fibronectin fibrils and inhibits ECM fibronectin endocytosis by inhibiting a5b1-integrin endocytosis. These data are the first to show that an ECM protein and its modifying enzyme can regulate integrin endocytosis. These data also show that integrin trafficking plays a major role in modulating ECM fibronectin remodeling. The dual dependence of ECM fibronectin turnover on extracellular proteolysis and endocytosis highlights the complex regulatory mechanisms that control ECM remodeling to ensure maintenance of proper tissue function.

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“…FUD binds to the N-terminal assembly domain of fibronectin and prevents the fibronectinfibronectin interactions that are essential for matrix assembly ) but does not affect fibronectin expression (Chiang et al, 2009; data not shown). The III-11C peptide derived from the III-11 module of fibronectin was used as a control (Bourdoulous et al, 1998;Chiang et al, 2009). Treatment of MSCs with FUD for 24 h in a monolayer culture blocked matrix assembly (Fig.…”

Section: Condensation Depends On Fibronectin Matrix Assemblymentioning

confidence: 92%

Fibronectin matrix assembly is essential for cell condensation during chondrogenesis

Singh

Schwarzbauer

2014

Journal of Cell Science

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Mesenchymal cell condensation is the initiating event in endochondral bone formation. Cell condensation is followed by differentiation into chondrocytes, which is accompanied by induction of chondrogenic gene expression. Gene mutations involved in chondrogenesis cause chondrodysplasias and other skeletal defects. Using mesenchymal stem cells (MSCs) in an in vitro chondrogenesis assay, we found that knockdown of the diastrophic dysplasia (DTD) sulfate transporter (DTDST, also known as SLC26A2), which is required for normal cartilage development, blocked cell condensation and caused a significant reduction in fibronectin matrix. Knockdown of fibronectin with small interfering RNAs (siRNAs) also blocked condensation. Fibrillar fibronectin matrix was detected prior to cell condensation, and its levels increased during and after condensation. Inhibition of fibronectin matrix assembly by use of the functional upstream domain (FUD) of adhesin F1 from Streptococcus pyogenes prevented cell condensation by MSCs and also by the chondrogenic cell line ATDC5. Our data show that cell condensation and induction of chondrogenesis depend on fibronectin matrix assembly and DTDST, and indicate that this transporter is required earlier in chondrogenesis than previously appreciated. They also raise the possibility that certain of the skeletal defects in DTD patients might derive from the link between DTDST, fibronectin matrix and condensation.

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Fibronectin Is an Important Regulator of Flow-Induced Vascular Remodeling

Cited by 147 publications

References 60 publications

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

MT1-MMP regulates the turnover and endocytosis of extracellular matrix fibronectin

Fibronectin matrix assembly is essential for cell condensation during chondrogenesis

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