scholarly journals Cyclic Stretch Induces Vascular Smooth Muscle Cells to Secrete Connective Tissue Growth Factor and Promote Endothelial Progenitor Cell Differentiation and Angiogenesis

2020 ◽  
Vol 8 ◽  
Author(s):  
Jing Yan ◽  
Wen-Bin Wang ◽  
Yang-Jing Fan ◽  
Han Bao ◽  
Na Li ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Connective Tissue ◽  
Vascular Injury ◽  
Tissue Growth ◽  
Cyclic Stretch ◽  
Endothelial Differentiation ◽  
Vascular Repair ◽  
Injury Model

Endothelial progenitor cells (EPCs) play a vital role in endothelial repair following vascular injury by maintaining the integrity of endothelium. As EPCs home to endothelial injury sites, they may communicate with exposed vascular smooth muscle cells (VSMCs), which are subjected to cyclic stretch generated by blood flow. In this study, the synergistic effect of cyclic stretch and communication with neighboring VSMCs on EPC function during vascular repair was investigated. In vivo study revealed that EPCs adhered to the injury site and were contacted to VSMCs in the Sprague–Dawley (SD) rat carotid artery injury model. In vitro, EPCs were cocultured with VSMCs, which were exposed to cyclic stretch at a magnitude of 5% (which mimics physiological stretch) and a constant frequency of 1.25 Hz for 12 h. The results indicated that stretched VSMCs modulated EPC differentiation into mature endothelial cells (ECs) and promoted angiogenesis. Meanwhile, cyclic stretch upregulated the mRNA expression and secretion level of connective tissue growth factor (CTGF) in VSMCs. Recombinant CTGF (r-CTGF) treatment promoted endothelial differentiation of EPCs and angiogenesis, and increased their protein levels of FZD8 and β-catenin. CTGF knockdown in VSMCs inhibited cyclic stretch-induced EPC differentiation into ECs and attenuated EPC tube formation via modulation of the FZD8/β-catenin signaling pathway. FZD8 knockdown repressed endothelial differentiation of EPCs and their angiogenic activity. Wnt signaling inhibitor decreased the endothelial differentiation and angiogenetic ability of EPCs cocultured with stretched VSMCs. Consistently, an in vivo Matrigel plug assay demonstrated that r-CTGF-treated EPCs exhibited enhanced angiogenesis; similarly, stretched VSMCs also induced cocultured EPC differentiation toward ECs. In a rat vascular injury model, r-CTGF improved EPC reendothelialization capacity. The present results indicate that cyclic stretch induces VSMC-derived CTGF secretion, which, in turn, activates FZD8 and β-catenin to promote both differentiation of cocultured EPCs into the EC lineage and angiogenesis, suggesting that CTGF acts as a key intercellular mediator and a potential therapeutic target for vascular repair.

Connective tissue growth factor and vascular endothelial growth factor from airway smooth muscle interact with the extracellular matrix

2006 ◽  
Vol 290 (1) ◽  
pp. L153-L161 ◽  
Author(s):  
Janette K. Burgess ◽  
Qi Ge ◽  
Maree H. Poniris ◽  
Sarah Boustany ◽  
Stephen M. Twigg ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Vascular Endothelial Growth Factor ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Connective Tissue ◽  
Airway Smooth Muscle ◽  
Connective Tissue Growth Factor ◽  
Tissue Growth ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Airway remodeling describes the structural changes that occur in the asthmatic airway that include airway smooth muscle hyperplasia, increases in vascularity due to angiogenesis, and thickening of the basement membrane. Our aim in this study was to examine the effect of transforming growth factor-β on the release of connective tissue growth factor and vascular endothelial growth factor from human airway smooth muscle cells derived from asthmatic and nonasthmatic patients. In addition we studied the immunohistochemical localization of these cytokines in the extracellular matrix after stimulating bronchial rings with transforming growth factor-β. Connective tissue growth factor and vascular endothelial growth factor were released from both cell types and colocalized in the surrounding extracellular matrix. Prostaglandin E2 inhibited the increase in connective tissue growth factor mRNA but augmented the release of vascular endothelial growth factor. Matrix metalloproteinase-2 decreased the amount of connective tissue growth factor and vascular endothelial growth factor, but not fibronectin deposited in the extracellular matrix. This report provides the first evidence that connective tissue growth factor may anchor vascular endothelial growth factor to the extracellular matrix and that this deposition is decreased by matrix metalloproteinase-2 and prostaglandin E2. This relationship has the potential to contribute to the changes that constitute airway remodeling, therefore providing a novel focus for therapeutic intervention in asthma.

Abstract 311: Osteogenic Transcription Factor Runx2 Represses Connective Tissue Growth Factor Gene Expression And TGFβ Signaling In Vascular Smooth Muscle Cells

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Toru Tanaka ◽  
Takehisa Shimizu ◽  
Norimichi Koitabashi ◽  
Hiroki Matsui ◽  
Hiroshi Doi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Transcription Factor ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Connective Tissue ◽  
Vascular Smooth Muscle Cells ◽  
Tissue Growth ◽  
Matrix Synthesis ◽  
Tgfβ Signaling

[Objective] Runx2, a key transcription factor in osteoblast differentiation, is expressed in calcified atherosclerotic plaques. We have recently shown that Runx2 represses vascular smooth muscle cells (VSMCs) differentiation and promotes their osteogenic differentiation. Connective tissue growth factor (CTGF) has been implicated in the progression to vulnerable plaque by inducing mononuclear cell chemotaxis and VSMCs apoptosis despite of its potent stimulatory effect on connective tissue cell the proliferation and extracellular matrix synthesis. To assess the role of Runx2 in the process of plaque development, we investigated the molecular mechanism of the CTGF gene expression by Runx2 in VSMCs. [Methods and Results] RT-PCR analyses showed that adenovirally overexpressed Runx2 significantly repressed the basal expression of the CTGF gene in human aortic SMCs (HASMCs). Consistent with this, knockdown of the Runx2 expression in HASMCs by small interfering RNA (siRNA) increased CTGF mRNA levels. Luciferase assays showed that Runx2 reduced the transcriptional activity of the CTGF promoter. Transfection of a series of 5′-deletion constructs revealed that Runx2 inhibited CTGF expression through the sequence element located at 5′ untranslated region of CTGF mRNA. We next examined the effects of Runx2 on the TGFβ-induced CTGF expression. Runx2 overexpression significantly repressed CTGF expression in HASMCs stimulated with TGFβ, and knockdown of Runx2 by siRNA enhanced the induction of CTGF expression in response to TGFβ. Runx2 repressed TGFβ-induced CTGF promoter activity through the sequence including Smad binding element (SBE). Overexpression of Runx2 significantly reduced TGFβ- and Smad3-mediated luciferase activity of Smad-dependent promoter which contains four copies of SBE. Biotinylated DNA pulldown assay using SBE of CTGF promoter showed that Runx2 formed a complex with Smad3 and Smad4. [Conclusion] Runx2 repressed basal and TGFβ-induced CTGF gene expression in VSMCs. Thus, in addition to the potential for inducing vascular calcification, Runx2 may affect plaque stability by modulating extracellular matrix synthesis through inhibiting CTGF gene expression and TGFβ signaling.

scholarly journals CCN2 (Connective Tissue Growth Factor) Promotes Fibroblast Adhesion to Fibronectin

2004 ◽  
Vol 15 (12) ◽  
pp. 5635-5646 ◽  
Author(s):  
Yunliang Chen ◽  
David J. Abraham ◽  
Xu Shi-wen ◽  
Jeremy D. Pearson ◽  
Carol M. Black ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Growth Factor ◽  
Protein Kinase ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Tissue Growth ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Fibroblast Adhesion

In vivo, CCN2 (connective tissue growth factor) promotes angiogenesis, osteogenesis, tissue repair, and fibrosis, through largely unknown mechanisms. In vitro, CCN2 promotes cell adhesion in a variety of systems via integrins and heparin sulfate proteoglycans (HSPGs). However, the physiological relevance of CCN2-mediated cell adhesion is unknown. Here, we find that HSPGs and the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase cascade are required for adult human dermal fibroblasts to adhere to CCN2. Endogenous CCN2 directly binds fibronectin and the fibronectin receptors integrins α4 β1 and α5 and syndecan 4. Using Ccn2-/- mouse embryonic fibroblasts, we show that loss of endogenous CCN2 results in impaired spreading on fibronectin, delayed α-smooth muscle actin stress fiber formation, and reduced ERK and focal adhesion kinase phosphorylation. These results suggest that a physiological role of CCN2 is to potentiate the ability of fibroblasts to spread on fibronectin, which may be important in modulating fibroblast adhesion to the provisional matrix during tissue development and wound healing. These results are consistent with the notion that a principal function of CCN2 is to modulate receptor/ligand interactions in vivo.

scholarly journals Gypenoside LXXV Promotes Cutaneous Wound Healing In Vivo by Enhancing Connective Tissue Growth Factor Levels Via the Glucocorticoid Receptor Pathway

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1595 ◽  
Author(s):  
Sungjoo Park ◽  
Eunsu Ko ◽  
Jun Hyoung Lee ◽  
Yoseb Song ◽  
Chang-Hao Cui ◽  
...  
Keyword(s):  
Wound Healing ◽  
Growth Factor ◽  
Connective Tissue ◽  
Wound Closure ◽  
Tissue Growth ◽  
Cutaneous Wound Healing ◽  
Cutaneous Wound ◽  
And Migration ◽  
Proliferation And Migration

Cutaneous wound healing is a well-orchestrated event in which many types of cells and growth factors are involved in restoring the barrier function of skin. In order to identify whether ginsenosides, the main active components of Panax ginseng, promote wound healing, the proliferation and migration activities of 15 different ginsenosides were tested by MTT assay and scratched wound closure assay. Among ginsenosides, gypenoside LXXV (G75) showed the most potent wound healing effects. Thus, this study aimed to investigate the effects of G75 on wound healing in vivo and characterize associated molecular changes. G75 significantly increased proliferation and migration of keratinocytes and fibroblasts, and promoted wound closure in an excision wound mouse model compared with madecassoside (MA), which has been used to treat wounds. Additionally, RNA sequencing data revealed G75-mediated significant upregulation of connective tissue growth factor (CTGF), which is known to be produced via the glucocorticoid receptor (GR) pathway. Consistently, the increase in production of CTGF was confirmed by western blot and ELISA. In addition, GR-competitive binding assay and GR translocation assay results demonstrated that G75 can be bound to GR and translocated into the nucleus. These results demonstrated that G75 is a newly identified effective component in wound healing.

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