Loss of SMAD3 Promotes Vascular Remodeling in Pulmonary Arterial Hypertension via MRTF Disinhibition

Zabini, Diana; Granton, Elise; Hu, Youli; Miranda, Maria Zena; Weichelt, Ulrike; Bonnet, Sandra Breuils; Morrell, Nicholas W.; Connelly, Kim A.; Provencher, Steeve; Ghanim, Bahil; Klepetko, Walter; Olschewski, Andrea; Kapùs, András; Kuebler, Wolfgang M.

doi:10.1164/rccm.201702-0386oc

Cited by 54 publications

(57 citation statements)

References 49 publications

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“…Migration of epicardial cells also exhibits a dependency on MRTF-SRF signaling (Trembley et al, 2015). Loss of SMAD3 promotes migration of human pulmonary arterial smooth muscle cells and endothelial cells through increased activation of MRTFA (Zabini et al, 2017). • Endothelial cells: Selective disruption of either SRF or the MRTFA and MRFTB genes in endothelial cells, when conditionally induced in neonatal and adult mice, causes a prominent reduction in actin-based filopodial processes, invasion of tip cells and angiogenesis in the retina (Franco et al, 2013;Weinl et al, 2013).…”

Section: Mechanisms Of Mrtf-dependent Regulation Of Cell Migration Srmentioning

confidence: 99%

SRF'ing and SAP'ing – the role of MRTF proteins in cell migration

Gau

Roy

2018

Journal of Cell Science

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Actin-based cell migration is a fundamental cellular activity that plays a crucial role in a wide range of physiological and pathological processes. An essential feature of the remodeling of actin cytoskeleton during cell motility is the de novo synthesis of factors involved in the regulation of the actin cytoskeleton and cell adhesion in response to growth-factor signaling, and this aspect of cell migration is critically regulated by serum-response factor (SRF)mediated gene transcription. Myocardin-related transcription factors (MRTFs) are key coactivators of SRF that link actin dynamics to SRF-mediated gene transcription. In this Review, we provide a comprehensive overview of the role of MRTF in both normal and cancer cell migration by discussing its canonical SRF-dependent as well as its recently emerged SRF-independent functions, exerted through its SAP domain, in the context of cell migration. We conclude by highlighting outstanding questions for future research in this field.

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Section: Mechanisms Of Mrtf-dependent Regulation Of Cell Migration Srmentioning

confidence: 99%

SRF'ing and SAP'ing – the role of MRTF proteins in cell migration

Gau

Roy

2018

Journal of Cell Science

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“…BMPR2 is closely entangled with other members of the TGF-β family, but the roles of many of the ligands and receptors in the TGF-β family are still underappreciated in PAH. Although bone morphogenetic protein (BMP) ligands and their receptors play an important role in disease progression and could function as therapeutic targets [ 11 ], agents effectively decreasing TGF-β1 activity, together with selective TGF-β ligand traps open up new treatment possibilities [ 12 , 13 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

TGF-β and BMPR2 Signaling in PAH: Two Black Sheep in One Family

Rol

Kurakula

Happé

et al. 2018

IJMS

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Knowledge pertaining to the involvement of transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling in pulmonary arterial hypertension (PAH) is continuously increasing. There is a growing understanding of the function of individual components involved in the pathway, but a clear synthesis of how these interact in PAH is currently lacking. Most of the focus has been on signaling downstream of BMPR2, but it is imperative to include the role of TGF-β signaling in PAH. This review gives a state of the art overview of disturbed signaling through the receptors of the TGF-β family with respect to vascular remodeling and cardiac effects as observed in PAH. Recent (pre)-clinical studies in which these two pathways were targeted will be discussed with an extended view on cardiovascular research fields outside of PAH, indicating novel future perspectives.

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“…SMAD2 and SMAD3 promote fibrosis induced by TGF-β signaling causing tissue fibrosis while SMAD7 acts as a negative modulator [70]. However, in PAH patients and in animal models of PAH, a loss of SMAD3 function increased pulmonary vascular remodeling by disinhibiting the myocardin-related transcription factor [56]. Nevertheless, pulmonary hypertension has not been described among patients with SMAD3 or SMAD4 mutations.…”

Section: Genes Potentially Related To Increased Cell Proliferationmentioning

confidence: 99%

Potential Molecular Pathways Related to Pulmonary Artery Aneurysm Development: Lessons to Learn from the Aorta

Nuche

Palomino-Doza

Arribas

et al. 2020

IJMS

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Pulmonary arterial hypertension (PAH) is a rare disease caused by pulmonary vascular remodeling. Current vasodilator treatments have substantially improved patients' survival. This improved survival has led to the appearance of complications related to conditions previously underdiagnosed or even ignored, such as pulmonary artery aneurysm (PAA). The presence of a dilated pulmonary artery has been shown to be related to an increased risk of sudden cardiac death among PAH patients. This increased risk could be associated to the development of left main coronary artery compression or pulmonary artery dissection. Nevertheless, very little is currently known about the molecular mechanisms related to PAA. Thoracic aortic aneurysm (TAA) is a well-known condition with an increased risk of sudden death caused by acute aortic dissection. TAA may be secondary to chronic exposure to classic cardiovascular risk factors. In addition, a number of genetic variants have been shown to be related to a marked risk of TAA and dissection as part of multisystemic syndromes or isolated familial TAA. The molecular pathways implied in the development of TAA have been widely studied and described. Many of these molecular pathways are involved in the pathogenesis of PAH and could be involved in PAA. This review aims to describe all these common pathways to open new research lines that could help lead to a better understanding of the pathophysiology of PAH and PAA and their clinical implications.

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Loss of SMAD3 Promotes Vascular Remodeling in Pulmonary Arterial Hypertension via MRTF Disinhibition

Abstract: Loss of SMAD3 presents a novel pathomechanism in PAH that promotes vascular cell proliferation and-via MRTF disinhibition-hypertrophy of huPASMCs, thereby reconciling the parallel induction of a synthetic and contractile huPASMC phenotype.

Cited by 54 publications

References 49 publications

SRF'ing and SAP'ing – the role of MRTF proteins in cell migration

SRF'ing and SAP'ing – the role of MRTF proteins in cell migration

TGF-β and BMPR2 Signaling in PAH: Two Black Sheep in One Family

Potential Molecular Pathways Related to Pulmonary Artery Aneurysm Development: Lessons to Learn from the Aorta

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