Activation and Migration of Adventitial Fibroblasts Contributes to Vascular Remodeling

Han, Xiao; Wu, Aiming; Wang, Jie; Chang, Hong; Zhao, Yizhou; Zhang, Yan; Mao, Yingqiu; Lou, Lixia; Gao, Yonghong; Zhang, Dongmei; Li, Tong; Yang, Tao; Wang, Lei; Feng, Cuiping; Zhao, Ming

doi:10.1002/ar.23793

Cited by 17 publications

(11 citation statements)

References 31 publications

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“…Similar findings were later reported by Han et al [51] showing that adventitial fibroblasts migrated to the media and intima on seventh day after balloon injury in the rat carotid artery. The results were obtained by direct labeling of adventitial fibroblasts using in vivo gene transfer technique, as well as transmission electron microscopy [51]. Furthermore, Dutzmann et al [52] discovered that early activation of adventitial fibroblasts after wire-induced injury in C57BL/6 mice stimulated their proliferation and release of proinflammatory cytokines and growth factors, and the subsequent proliferation of VSMC, resulting in neointima formation [52].…”

Section: Contribution Of Adventitial Fibroblasts To Vascular Pathologysupporting

confidence: 91%

“…On the contrary, in the arteries that were not injured, the expression of LacZ and enzymatic activity of β-galactosidase were restricted to the adventitia [50]. Similar findings were later reported by Han et al [51] showing that adventitial fibroblasts migrated to the media and intima on seventh day after balloon injury in the rat carotid artery. The results were obtained by direct labeling of adventitial fibroblasts using in vivo gene transfer technique, as well as transmission electron microscopy [51].…”

Section: Contribution Of Adventitial Fibroblasts To Vascular Pathologysupporting

confidence: 86%

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The Role of Fibroblasts in Atherosclerosis Progression

Kuret¹,

Sodin‐Šemrl²

2021

Biochemistry

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The following chapter addresses vascular fibroblasts in a healthy, quiescent state, as well during vascular inflammation, focusing on atherosclerosis. The development of atherosclerosis, an inflammatory disease of medium- and large-sized arteries, has traditionally been viewed as an “inside-out” mechanism, with prominent roles of the innermost layer of the artery, consisting of endothelial cells. However, emerging evidence suggests a new paradigm of “outside-in” mechanism, including an earlier role for fibroblasts, constituents of the outermost adventitial layer of the artery. Phenotypic and functional changes of fibroblasts in adventitia may even occur prior to, or alongside endothelial activation. Activated adventitial fibroblasts, implicated in atherosclerosis progression, begin to transform into myofibroblasts, upregulate production of different proinflammatory cytokines, chemokines, growth factors, proteolytic enzymes, extracellular matrix proteins and reactive oxygen species, leading to extensive matrix remodeling, chemotaxis and recruitment of immune cells. Due to their suitable location for drug delivery systems, preventing fibroblast activation, modulating their activity or inducing myofibroblast dedifferentiation could represent a promising therapeutic approach for atherosclerosis regression.

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Section: Contribution Of Adventitial Fibroblasts To Vascular Pathologysupporting

confidence: 91%

Section: Contribution Of Adventitial Fibroblasts To Vascular Pathologysupporting

confidence: 86%

The Role of Fibroblasts in Atherosclerosis Progression

Kuret¹,

Sodin‐Šemrl²

2021

Biochemistry

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“…In AFBs, there were significant losses in α-SMA due to calcification. In other stressful situations, fibroblasts express more α-SMA and transition to a myofibroblast or “activated fibroblast” phenotype, characterized by a loss of markers such as vimentin ( Li et al, 2015 ; Han et al, 2018 ). Our findings would suggest that the AFBs are undergoing a similar phenotype transition.…”

Section: Discussionmentioning

confidence: 99%

“…AFBs reside in the vessel’s outermost layer, where they cohabitate with vascular progenitor cells, pericytes, and immune cells ( Kuwabara and Tallquist, 2017 ). Normally, AFBs are responsible for extracellular matrix deposition and secretion of cytokines and chemokines; however, AFBs can differentiate to “activated fibroblasts” under stressful conditions myofibroblasts, where they begin expressing α-SMA and increase migration toward sites of injury ( Baum and Duffy, 2011 ; Han et al, 2018 ). In calcification conditions, AFBs express osteogenic proteins, such as OCN, ALP, Msx2, and CBFα1, similar to VSMCs ( Simionescu et al, 2007 ; Lai et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

RAGE Differentially Altered in vitro Responses in Vascular Smooth Muscle Cells and Adventitial Fibroblasts in Diabetes-Induced Vascular Calcification

Kennon

Stewart

2021

Front. Physiol.

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The Advanced Glycation End-Products (AGE)/Receptor for AGEs (RAGE) signaling pathway exacerbates diabetes-mediated vascular calcification (VC) in vascular smooth muscle cells (VSMCs). Other cell types are involved in VC, such as adventitial fibroblasts (AFBs). We hope to elucidate some of the mechanisms responsible for differential signaling in diabetes-mediated VC with this work. This work utilizes RAGE knockout animals and in vitro calcification to measure calcification and protein responses. Our calcification data revealed that VSMCs calcification was AGE/RAGE dependent, yet AFBs calcification was not an AGE-mediated RAGE response. Protein expression data showed VSMCs lost their phenotype marker, α-smooth muscle actin, and had a higher RAGE expression over non-diabetics. RAGE knockout (RKO) VSMCs did not show changes in phenotype markers. P38 MAPK, a downstream RAGE-associated signaling molecule, had significantly increased activation with calcification in both diabetic and diabetic RKO VSMCs. AFBs showed a loss in myofibroblast marker, α-SMA, due to calcification treatment. RAGE expression decreased in calcified diabetic AFBs, and P38 MAPK activation significantly increased in diabetic and diabetic RKO AFBs. These findings point to potentially an alternate receptor mediating the calcification response in the absence of RAGE. Overall, VSMCs and AFBs respond differently to calcification and the application of AGEs.

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“…[3][4][5][6][7][8] However, other than VSMCs and VECs, the role of the remaining cell types in the vascular wall, especially the vascular adventitial fibroblasts (VAFs), in the neointima formation gained attention in recent years. [9][10][11] A series of studies have shown that after vascular injury, similar to VSMCs, VAFs are also activated and undergo a phenotypic change into myofibroblasts to secrete multiple cytokines and growth factors, like IL6, CXCL1, OPN, TGF-β1, MCP-1, VEGF and reactive oxygen species (ROS). Some of them have been shown to promote proliferation of VSMCs in the medial layer.…”

Section: Introductionmentioning

confidence: 99%

Vascular Adventitial Fibroblasts-Derived FGF10 Promotes Vascular Smooth Muscle Cells Proliferation and Migration in vitro and the Neointima Formation in vivo

Chen¹,

Chen²,

Jiang³

et al. 2021

JIR

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Background: Activation of vascular adventitial fibroblasts (VAFs) upon vascular injury contributes greatly to the medial vascular smooth muscle cells (VSMCs) proliferation, migration and the subsequent neointima formation. A number of factors including fibroblast growth factors (FGFs) have been shown to control VSMC growth, proliferation and phenotypic switching, suggesting that they may function as paracrine signals for VAFs to modulate VSMCs functions. However, little is known about the signaling molecule(s) and its mechanism of action. This study is set to identify which and how FGF family members are involved in VAFs mediated vascular remodeling. Methods: We used qPCR, Western blot and Immunohistochemistry to observe the spatiotemporal expression of FGF10 and FGFR2 in injured vascular tissue. The proliferation and migration assays of VSMCs were performed in a co-culture system. The activation of signaling pathway was detected by Western blot, immunohistochemistry and immunofluorescence. Hematoxylin-eosin and immunofluorescence were used to assess the effects of exogenous FGF10 and siFGF10 on the neointima formation. Results: The expression of FGF10 and FGFR2 were increased from day 3 through day 14 post injury. FGF10 was significantly upregulated in adventitia, and FGFR2 was detected in both media and neointima after injury. In vitro, FGF10 was most prominently expressed in VAFs and FGFR2 was significantly expressed in VSMCs. Both were regulated by PDGF. Co-culture of VAFs and VSMCs in vitro showed that VAF-derived FGF10 promoted the proliferation and migration of VSMCs. PDGF could synergistically enhance the process. VAF-derived FGF10 can significantly activate the FGFR2 in VSMCs and furthermore significantly activate the downstream MAPK/PI3K-AKT signaling pathways. Delivery of exogenous FGF10 potentiated the neointima formation, while siFGF10 attenuated the neointima formation. Conclusion: VAFs-derived FGF10 promoted the proliferation and migration of VSMCs and neointima formation, and FGF10-FGFR2 signaling triggered the activation of MAPK/PI3K-AKT pathways in VSMCs and PDGF synergistically amplified FGF10 signaling.

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Activation and Migration of Adventitial Fibroblasts Contributes to Vascular Remodeling

Cited by 17 publications

References 31 publications

The Role of Fibroblasts in Atherosclerosis Progression

The Role of Fibroblasts in Atherosclerosis Progression

RAGE Differentially Altered in vitro Responses in Vascular Smooth Muscle Cells and Adventitial Fibroblasts in Diabetes-Induced Vascular Calcification

Vascular Adventitial Fibroblasts-Derived FGF10 Promotes Vascular Smooth Muscle Cells Proliferation and Migration in vitro and the Neointima Formation in vivo

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