Smooth muscle cell–specific fibronectin-EDA mediates phenotypic switching and neointimal hyperplasia

Jain, Manish; Dhanesha, Nirav; Doddapattar, Prakash; Chorawala, Mehul R.; Nayak, Manasa K.; Cornelissen, Anne; Guo, Liang; Finn, Aloke V.; Lentz, Steven R.; Chauhan, Anil K.

doi:10.1172/jci124708

Cited by 53 publications

(34 citation statements)

References 55 publications

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“…In fact, the aforementioned studies focused on the effect of exogenous FN-EDA on HSCs; however, our data, including some unpublished data, suggested that HSCs were the dominant source of FN-EDA during hepatic fibrosis and that interfering with FN-EDA expression in vitro decreased the expression of α-SMA and VEGFA but not collagen, indicating that HSC derived FN-EDA, rather than exogenous FN-EDA, is important to maintain HSC activation. A recent study reported that specific deletion of FN-EDA in smooth muscle cells, but not in endothelial cells, reduced smooth muscle cell phenotypic switching highlighting the importance of fibroblast endogenous derived FN-EDA 33 . Traditionally, FN-EDA is known as a component of extra matrix that assembles into insoluble fibrils 53 .…”

Section: Discussionmentioning

confidence: 99%

“…In spite of collagen is the quantitatively dominant matrix component in many fibrosis diseases, fibronectin is an early and important component which is upregulated in many fibrotic diseases and even considered as a fibrosis marker, there were limited investigation of its specific isoform and function. FN-EDA is reportedly upregulated and participated in fibrosis process, but most of the studies focus its role on activating fibroblasts 19,20,33 . A delicate designed research indicated that FN-EDA could promote only HSC motility not activation or differentiation while CCl 4 -induced EDA KO male mice did have less fibrosis and α-SMA expression 27 .…”

Section: Discussionmentioning

confidence: 99%

“…Our previous study demonstrated that FN is overexpressed in HSCs in mouse hepatic fibrosis. As EDA and EDB are the segments of FN unique to pathological states and are independently expressed due to alternative splicing 32,33 , we first detected their expression in normal and fibrotic livers. qRT-PCR analysis showed that EDA expression was significantly increased in the fibrotic group versus the healthy group ( Fig.…”

Section: Fn-eda Expression Was Elevated In Hepatic Fibrosis and Positmentioning

confidence: 99%

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FN-EDA mediates angiogenesis of hepatic fibrosis via integrin-VEGFR2 in a CD63 synergetic manner

Xie

et al. 2020

Cell Death Discov.

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Pathological angiogenesis is an important component of hepatic fibrosis along with fibrous deposition, but its role is not well understood. Here, we demonstrated that fibronectin containing extra domain A(FN-EDA), a fibronectin splice variant highly expressed in hepatic fibrosis, mediated angiogenesis in disease progression. FN-EDA was positively correlated with pathological angiogenesis in hepatic fibrosis, and a reduction in FN-EDA expression was associated with diminished intrahepatic angiogenesis and fibrosis. FN-EDA mostly colocalized with hepatic stellate cells (HSCs) and interference or blockage of FN-EDA attenuated migration and tube formation in co-cultured endothelial cells. Mechanistic studies indicated that FN-EDA was secreted to promote phosphorylation of VEGFR2 with the assistance of integrin and CD63. Targeting FN-EDA-integrin combination postponed the progression of hepatic angiogenesis and fibrosis in vivo. These results indicated that FN-EDA plays an emerging role in angiogenesis in hepatic fibrosis and could be a potential therapeutic intervention for the disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Fn-eda Expression Was Elevated In Hepatic Fibrosis and Positmentioning

confidence: 99%

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FN-EDA mediates angiogenesis of hepatic fibrosis via integrin-VEGFR2 in a CD63 synergetic manner

Xie

et al. 2020

Cell Death Discov.

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“…Fibronectin plays a role in cellular processes, hemostasis, and thrombosis [ 52 ]. Following arterial injuries, SMCs are activated, and fibronectin is deposited around proliferative cells in the media and intima: a phenomenon similar to neointimal formation [ 53 ].…”

Section: Mechanisms Of Anatomical Closurementioning

confidence: 99%

Molecular Mechanisms Underlying Remodeling of Ductus Arteriosus: Looking beyond the Prostaglandin Pathway

Hsu

Lin

Liu

et al. 2021

IJMS

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The ductus arteriosus (DA) is a physiologic vessel crucial for fetal circulation. As a major regulating factor, the prostaglandin pathway has long been the target for DA patency maintenance or closure. However, the adverse effect of prostaglandins and their inhibitors has been a major unsolved clinical problem. Furthermore, a significant portion of patients with patent DA fail to respond to cyclooxygenase inhibitors that target the prostaglandin pathway. These unresponsive medical patients ultimately require surgical intervention and highlight the importance of exploring pathways independent from this well-recognized prostaglandin pathway. The clinical limitations of prostaglandin-targeting therapeutics prompted us to investigate molecules beyond the prostaglandin pathway. Thus, this article introduces molecules independent from the prostaglandin pathway based on their correlating mechanisms contributing to vascular remodeling. These molecules may serve as potential targets for future DA patency clinical management.

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“…This experiment highlights the potentials of gene therapy in targeting matrix components in ductal-dependent congenital heart defects. Furthermore, not only is FN translation implicated in intimal thickening, aberrant posttranslational modifications of FN have been reported to be implicated in the settings of vasculature remodeling of aneurysms and arterial injury [ 12 , 51 ].…”

Section: Role Of Ecm In Da Remodelingmentioning

confidence: 99%

Role of Extracellular Matrix in Pathophysiology of Patent Ductus Arteriosus: Emphasis on Vascular Remodeling

Lin

Yeh

Hsu

2020

IJMS

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The ductus arteriosus (DA) is a shunt vessel between the aorta and the pulmonary artery during the fetal period that is essential for the normal development of the fetus. Complete closure usually occurs after birth but the vessel might remain open in certain infants, as patent ductus arteriosus (PDA), causing morbidity or mortality. The mechanism of DA closure is a complex process involving an orchestration of cell–matrix interaction between smooth muscle cells (SMC), endothelial cells, and extracellular matrix (ECM). ECM is defined as the noncellular component secreted by cells that consists of macromolecules such as elastin, collagens, proteoglycan, hyaluronan, and noncollagenous glycoproteins. In addition to its role as a physical scaffold, ECM mediates diverse signaling that is critical in development, maintenance, and repair in the cardiovascular system. In this review, we aim to outline the current understandings of ECM and its role in the pathophysiology of PDA, with emphasis on DA remodeling and highlight future outlooks. The molecular diversity and plasticity of ECM present a rich array of potential therapeutic targets for the management of PDA.

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Smooth muscle cell–specific fibronectin-EDA mediates phenotypic switching and neointimal hyperplasia

Cited by 53 publications

References 55 publications

FN-EDA mediates angiogenesis of hepatic fibrosis via integrin-VEGFR2 in a CD63 synergetic manner

FN-EDA mediates angiogenesis of hepatic fibrosis via integrin-VEGFR2 in a CD63 synergetic manner

Molecular Mechanisms Underlying Remodeling of Ductus Arteriosus: Looking beyond the Prostaglandin Pathway

Role of Extracellular Matrix in Pathophysiology of Patent Ductus Arteriosus: Emphasis on Vascular Remodeling

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