Hypoxia Upregulates NOTCH3 Signaling Pathway to Promote Endothelial-Mesenchymal Transition in Pulmonary Artery Endothelial Cells

Background. To investigate the effect of hypoxia on pulmonary artery endothelial cells and the role of NOTCH3 in endothelial-mesenchymal transition (EnMT) and to provide a research model for pulmonary disease and explain the pathogenesis of the pulmonary disease. Methods. Pulmonary artery endothelial cells were divided into two groups and cultured in normoxic and hypoxic environments, respectively. QPCR, western blot, and immunofluorescence were used to detect endothelial cell-specific marker protein and mRNA expression in each group, and the ability of endothelial cells migration was evaluated by scratch and transwell experiment. Results. The pulmonary artery endothelial cells in the normoxic group presented a typical pebble-like arrangement, and the endothelial cells in hypoxic culture showed a long spindle appearance. Hypoxia induced high expression of NOTCH3, Jagged-1, Hes1, c-Src, and CSL. Immunofluorescence showed that endothelial cells in hypoxic culture began to express the α-SMA, and the expression of vWF increased with hypoxia. Cell viability, scratch, and transwell results showed that endothelial cells in the hypoxic group were more capable of viability and migration than those in the normoxic group. The induction of EnMT by hypoxia can be inhibited by using notch3-specific inhibitor DAPT and Jagged-1. This study also found that miR-7-5p can regulate endothelial NOTCH3, indicating that miRNA is also involved in the process of endothelial-mesenchymal transformation. Conclusion. Hypoxia promotes the transformation of endothelial cells into mesenchymal cells by opening the NOTCH3 pathway, which lays the foundation for disease progression or clinical prognosis, and is of great significance in the treatment of diseases.

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ATG7-SILENCING INDUCES ENDOTHELIAL-MESENCHYMAL TRANSITION-LIKE PHENOTYPIC SWITCHING IN HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS

Canadian Journal of Cardiology ◽

10.1016/j.cjca.2014.07.395 ◽

2014 ◽

Vol 30 (10) ◽

pp. S233

Author(s):

K.K. Singh ◽

F. Lovren ◽

A. Quan ◽

Y. Pan ◽

H. Teoh ◽

...

Keyword(s):

Endothelial Cells ◽

Umbilical Vein ◽

Phenotypic Switching ◽

Mesenchymal Transition ◽

Human Umbilical Vein ◽

Umbilical Vein Endothelial Cells ◽

Endothelial Mesenchymal Transition

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Abstract 222: Dkk1 and Msx2-Wnt7b Signaling Reciprocally Regulate the Endothelial-Mesenchymal Transition in Aortic Endothelial Cells

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a222 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Su-Li Cheng ◽

Jian-su Shao ◽

Abraham Behrmann ◽

Karen Krchma ◽

Dwight A Towler

Keyword(s):

Endothelial Cells ◽

Mesenchymal Cell ◽

Type I ◽

Cuboidal Cell ◽

Aortic Endothelial Cells ◽

Mesenchymal Transition ◽

Cell Responses ◽

The Impact ◽

Endothelial Mesenchymal Transition ◽

Aortic Endothelial

Objective Endothelial cells (ECs) can undergo an endothelial-mesenchymal transition (EndMT) during tissue fibrosis. Wnt- and Msx2-regulated signals participate in arteriosclerotic calcification and fibrosis. We studied the impact of Wnt7, Msx2, and Dkk1 (Wnt7 antagonist) on EndMT in primary aortic endothelial cells (AoECs). Methods and Results Transduction of AoECs with vectors expressing Dkk1 suppressed EC differentiation and induced a mineralizing myofibroblast phenotype. Dkk1 suppressed claudin 5, PECAM, cadherin 5 (Cdh5), Tie1 and Tie2. Dkk1 converted the cuboidal cell monolayer into a spindle-shaped multilayer and inhibited EC cord formation. Myofibrogenic and osteogenic markers - e.g., SM22, type I collagen, Osx, Runx2, alkaline phosphatase – were upregulated by Dkk1 via activin-like kinase / Smad pathways. Dkk1 increased fibrosis and mineralization of AoECs cultured under osteogenic conditions - the opposite of mesenchymal cell responses. Msx2 and Wnt7b maintained the “cobblestone” morphology of differentiated ECs and promoted EC marker expression. Deleting EC Wnt7b with the Cdh5-Cre transgene in Wnt7b(fl/fl);LDLR-/- mice upregulated aortic osteogenic genes (Osx, Sox9, Runx2, Msx2) and nuclear pSmad1/5, and increased collagen accumulation. Conclusions Dkk1 enhances EndMT in AoECs, while Msx2-Wnt7 signals stabilize EC phenotype. EC responses to Dkk1, Wnt7b, and Msx2 are the opposite of mesenchymal cell responses, coupling EC phenotypic stability with osteofibrogenic predilection during arteriosclerosis.

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Liraglutide Inhibits Endothelial-to-Mesenchymal Transition and Attenuates Neointima Formation after Endovascular Injury in Streptozotocin-Induced Diabetic Mice

Cells ◽

10.3390/cells8060589 ◽

2019 ◽

Vol 8 (6) ◽

pp. 589 ◽

Cited By ~ 3

Author(s):

Tzu-Hsien Tsai ◽

Chien-Ho Lee ◽

Cheng-I Cheng ◽

Yen-Nan Fang ◽

Sheng-Ying Chung ◽

...

Keyword(s):

Endothelial Cells ◽

Morphological Changes ◽

Umbilical Vein ◽

Vascular Complications ◽

Specific Marker ◽

Neointima Formation ◽

Diabetic Mice ◽

Mesenchymal Transition ◽

Compound C ◽

Endothelial To Mesenchymal Transition

Hyperglycaemia causes endothelial dysfunction, which is the initial process in the development of diabetic vascular complications. Upon injury, endothelial cells undergo an endothelial-to-mesenchymal transition (EndMT), lose their specific marker, and gain mesenchymal phenotypes. This study investigated the effect of liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, on EndMT inhibition and neointima formation in diabetic mice induced by streptozotocin. The diabetic mice with a wire-induced vascular injury in the right carotid artery were treated with or without liraglutide for four weeks. The degree of neointima formation and re-endothelialisation was evaluated by histological assessments. Endothelial fate tracing revealed that endothelium-derived cells contribute to neointima formation through EndMT in vivo. In the diabetic mouse model, liraglutide attenuated wire injury-induced neointima formation and accelerated re-endothelialisation. In vitro, a high glucose condition (30 mmol/L) triggered morphological changes and mesenchymal marker expression in human umbilical vein endothelial cells (HUVECs), which were attenuated by liraglutide or Activin receptor-like 5 (ALK5) inhibitor SB431542. The inhibition of AMP-activated protein kinase (AMPK) signaling by Compound C diminished the liraglutide-mediated inhibitory effect on EndMT. Collectively, liraglutide was found to attenuate neointima formation in diabetic mice partially through EndMT inhibition, extending the potential therapeutic role of liraglutide.

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Correction to: Matrix metalloproteinase 9 induces endothelial-mesenchymal transition via Notch activation in human kidney glomerular endothelial cells

BMC Molecular and Cell Biology ◽

10.1186/s12860-020-00318-6 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Ye Zhao ◽

Xi Qiao ◽

Lihua Wang ◽

Tian Kui Tan ◽

Hong Zhao ◽

...

Keyword(s):

Endothelial Cells ◽

Matrix Metalloproteinase ◽

Human Kidney ◽

Matrix Metalloproteinase 9 ◽

Mesenchymal Transition ◽

Glomerular Endothelial Cells ◽

Metalloproteinase 9 ◽

Endothelial Mesenchymal Transition ◽

Notch Activation

An amendment to this paper has been published and can be accessed via the original article.

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Gremlin-1 is a key regulator of endothelial-to-mesenchymal transition in human pulmonary artery endothelial cells

Experimental Cell Research ◽

10.1016/j.yexcr.2020.111941 ◽

2020 ◽

Vol 390 (1) ◽

pp. 111941 ◽

Cited By ~ 2

Author(s):

Yunxia Zhang ◽

Meng Zhang ◽

Wanmu Xie ◽

Jun Wan ◽

Xincao Tao ◽

...

Keyword(s):

Endothelial Cells ◽

Pulmonary Artery ◽

Mesenchymal Transition ◽

Endothelial To Mesenchymal Transition ◽

Human Pulmonary Artery ◽

Gremlin 1

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A New Role for the Aldosterone/Mineralocorticoid Receptor Pathway in the Development of Mitral Valve Prolapse

Circulation Research ◽

10.1161/circresaha.119.316427 ◽

2020 ◽

Vol 127 (3) ◽

Cited By ~ 1

Author(s):

Jaime Ibarrola ◽

Amaia Garcia-Peña ◽

Lara Matilla ◽

Benjamin Bonnard ◽

Rafael Sádaba ◽

...

Keyword(s):

Endothelial Cells ◽

Mitral Valve ◽

Mitral Valve Prolapse ◽

Mineralocorticoid Receptor ◽

Cell Activation ◽

Cardiac Fibrosis ◽

Interstitial Cell ◽

Activation Markers ◽

Mesenchymal Transition ◽

Endothelial Mesenchymal Transition

Rationale: Mitral valve prolapse (MVP) is one of the most common valvular disorders. However, the molecular and cellular mechanisms involved in fibromyxomatous changes in the mitral leaflet tissue have not been elucidated. Aldosterone (Aldo) promotes fibrosis in myocardium, and MR (mineralocorticoid receptor) antagonists (MRAs) improve cardiac function by decreasing cardiac fibrosis. Objective: We investigated the role of the Aldo/MR in the fibromyxomatous modifications associated with MVP. Methods and Results: Aldo enhanced valvular interstitial cell activation markers and induced endothelial-mesenchymal transition in valvular endothelial cells, resulting in increased proteoglycan secretion. MRA blocked all the above effects. Cytokine arrays showed CT-1 (cardiotrophin-1) to be a mediator of Aldo-induced valvular interstitial cell activation and proteoglycan secretion and CD (cluster of differentiation) 14 to be a mediator of Aldo-induced endothelial-mesenchymal transition and proteoglycan secretion in valvular endothelial cells. In an experimental mouse model of MVP generated by nordexfenfluramine administration, MRA treatment reduced mitral valve thickness and proteoglycan content. Endothelial-specific MR deletion prevented fibromyxomatous changes induced by nordexfenfluramine administration. Moreover, proteoglycan expression was slightly lower in the mitral valves of MVP patients treated with MRA. Conclusions: These findings demonstrate, for the first time, that the Aldo/MR pathway regulates the phenotypic, molecular, and histological changes of valvular interstitial cells and valvular endothelial cells associated with MVP development. MRA treatment appears to be a promising option to reduce fibromyxomatous alterations in MVP.

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Endothelial-Mesenchymal Transition Occurs during Embryonic Pulmonary Artery Development

Endothelium ◽

10.1080/10623320500227283 ◽

2005 ◽

Vol 12 (4) ◽

pp. 193-200 ◽

Cited By ~ 64

Author(s):

Enrique Arciniegas ◽

Carmen Yudith Neves ◽

Luz Marina Carrillo ◽

Edgar A. Zambrano ◽

Richard Ramírez

Keyword(s):

Pulmonary Artery ◽

Mesenchymal Transition ◽

Endothelial Mesenchymal Transition

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When the endothelium scores an own goal: endothelial cells actively augment metastatic extravasation through endothelial-mesenchymal transition

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00042.2016 ◽

2016 ◽

Vol 310 (9) ◽

pp. H1055-H1063 ◽

Cited By ~ 19

Author(s):

Ákos Gasparics ◽

László Rosivall ◽

István A. Krizbai ◽

Attila Sebe

Keyword(s):

Endothelial Cells ◽

Tumor Cells ◽

Metastatic Tumor ◽

Therapeutic Approaches ◽

Mesenchymal Transition ◽

New Therapeutic Approaches ◽

Pathological Conditions ◽

Junctional Protein ◽

Endothelial Mesenchymal Transition ◽

Organ Fibrosis

Endothelial-mesenchymal transition (EndMT) is an important mechanism during organ development and in certain pathological conditions. For example, EndMT contributes to myofibroblast formation during organ fibrosis, and it has been identified as an important source of cancer-associated fibroblasts, facilitating tumor progression. Recently, EndMT was proposed to modulate endothelial function during intravasation and extravasation of metastatic tumor cells. Evidence suggests that endothelial cells are not passive actors during transendothelial migration (TEM) of cancer cells, as there are profound changes in endothelial junctional protein expression, signaling, permeability, and contractility. This review describes these alterations in endothelial characteristics during TEM of metastatic tumor cells and discusses them in the context of EndMT. EndMT could play an important role during metastatic intravasation and extravasation, a novel hypothesis that may lead to new therapeutic approaches to tackle metastatic disease.

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