Endothelial-Mesenchymal Transition in Vascular Calcification of Ins2Akita/+ Mice

Guihard, Pierre; Yao, Jiayi; Blázquez‐Medela, Ana M.; Iruela‐Arispe, M. Luisa; Boström, Kristina I.; Yao, Yucheng

doi:10.1371/journal.pone.0167936

Cited by 25 publications

(31 citation statements)

References 55 publications

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“…Previous studies have shown that ECs with mesenchymal and stem cell-like characteristics contribute to cerebral cavernous malformation, atherosclerosis, and the human genetic disorder fibrodysplasia ossificans progressiva (14,18,34). Moreover, ECs undergoing mesenchymal differentiation have been traced in studies of vascular calcification, where ECs gain multipotency and contribute osteoprogenitors to the calcifying process (17,22,35,36). Here, we show the emergence of mesenchymal stem cell markers in the endothelium of cerebral AVMs, which indicate a change in the endothelial fate through EndMTs.…”

Section: Discussionsupporting

confidence: 57%

Elevated endothelial Sox2 causes lumen disruption and cerebral arteriovenous malformations

Yao¹,

Wu²,

Zhang³

et al. 2019

Journal of Clinical Investigation

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Section: Discussionsupporting

confidence: 57%

Elevated endothelial Sox2 causes lumen disruption and cerebral arteriovenous malformations

Yao¹,

Wu²,

Zhang³

et al. 2019

Journal of Clinical Investigation

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“…We next aimed to validate our findings in vivo using an animal model of atherosclerosis. The contribution of EndMT to vascular calcification and atherosclerosis has been investigated in different animal models, including LDLR −/− , ApoE‐deficient, and Ins Akita mice . The ApoE3Leiden mice constitute a valuable model of diet‐induced atherosclerosis with a human‐like lipoprotein profile when fed a high‐fat diet .…”

Section: Resultsmentioning

confidence: 99%

“…The identification of patients at increased risk of acute coronary events associated with vascular calcification, who may benefit from intensified preventative measures and for monitoring therapeutic efficacy, is a major ongoing challenge . Recent publications have suggested that ECs directly contribute to vascular calcification through EndMT . We investigated the interplay between inflammatory cytokines and BMPs, a subfamily of the TGF‐β family, in ECs.…”

Section: Discussionmentioning

confidence: 99%

Inflammation induces endothelial‐to‐mesenchymal transition and promotes vascular calcification through downregulation of BMPR2

Sánchez‐Duffhues

Vinuesa

Pol

et al. 2019

The Journal of Pathology

142

106

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Endothelial‐to‐mesenchymal transition (EndMT) has been unveiled as a common cause for a multitude of human pathologies, including cancer and cardiovascular disease. Vascular calcification is a risk factor for ischemic vascular disorders and slowing calcification may reduce mortality in affected patients. The absence of early biomarkers hampers the identification of patients at risk. EndMT and vascular calcification are induced upon cooperation between distinct stimuli, including inflammatory cytokines and transforming growth factor beta (TGF‐β) family members. However, how these signaling pathways interplay to promote cell differentiation and eventually vascular calcification is not well understood. Using in vitro and ex vivo analysis in animal models and patient‐derived tissues, we have identified that the pro‐inflammatory cytokines tumor necrosis factor alpha (TNF‐α) and interleukin‐1 beta (IL‐1β) induce EndMT in human primary aortic endothelial cells, thereby sensitizing them for BMP‐9‐induced osteogenic differentiation. Downregulation of the BMP type II receptor BMPR2 is a key event in this process. Rather than compromising BMP canonical signal transduction, loss of BMPR2 results in decreased JNK signaling in ECs, thus enhancing BMP‐9‐induced mineralization. Altogether, our results point at the BMPR2–JNK signaling axis as a key pathway regulating inflammation‐induced EndMT and contributing to calcification. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…Guihard et al showed that the CD31 + CD45 ‐ sorted cells from the aorta of those mice exhibited increased expression of multipotent factors, including Sox‐2 , and that the endothelial specific deletion of Sox‐2 prevented aortic calcification. Also in this model, the pharmacological inhibition of serine proteases using diisopropyl fluorophosphate (DFP) blocked aortic calcification (Guihard et al, ).…”

Section: Endmt In Cardiovascular Disordersmentioning

confidence: 98%

Endothelial‐to‐mesenchymal transition in cardiovascular diseases: Developmental signaling pathways gone awry

Sánchez‐Duffhues

Vinuesa

Dijke

2017

Developmental Dynamics

124

113

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The process named endothelial-to-mesenchymal transition (EndMT) was observed for the first time during the development of the chicken embryo several decades ago. Of interest, accumulating evidence suggests that EndMT plays a critical role in the onset and progression of multiple postnatal cardiovascular diseases. EndMT is controlled by a set of developmental signaling pathways, very similar to the process of epithelial-to-mesenchymal transition, which determine the activity of several EndMT transcriptional effectors. Once activated, these EndMT effectors regulate the expression of endothelial-and mesenchymalspecific genes, in part by interacting with specific motifs in promoter regions, eventually leading to the down-regulation of endothelial-specific features and acquisition of a fibroblast-like phenotype. Important technical advances in lineage tracing methods combined with experimental mouse models demonstrated the pathophysiological importance of EndMT for human diseases. In this review, we discuss the major signal transduction pathways involved in the activation and regulation of the EndMT program. Furthermore, we will review the latest discoveries on EndMT, focusing on cardiovascular diseases, and in particular on its role in vascular calcification, pulmonary arterial hypertension, and organ fibrosis. Developmental Dynamics 247:492-508,

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Endothelial-Mesenchymal Transition in Vascular Calcification of Ins2Akita/+ Mice

Cited by 25 publications

References 55 publications

Elevated endothelial Sox2 causes lumen disruption and cerebral arteriovenous malformations

Elevated endothelial Sox2 causes lumen disruption and cerebral arteriovenous malformations

Inflammation induces endothelial‐to‐mesenchymal transition and promotes vascular calcification through downregulation of BMPR2

Endothelial‐to‐mesenchymal transition in cardiovascular diseases: Developmental signaling pathways gone awry

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