c-Met–mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma

Introduction: Pulmonary arterial hypertension (PAH) is a disaster disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Hypothesis: We hypothesis that endothelial plasticity or distinct cell populations are critical for obstructive vascular remodeling in the pathogenesis of PAH. Methods: Here we applied single-cell RNA sequencing (ScRNA-seq) to profile the pulmonary cells in a severe mouse model ( Egln1 Tie2Cre mice) of PAH. Human hPAEC from idiopathic PAH patients and healthy donors were used to measure FABP4 and FABP5 expression. siRNA mediated knockdown of FABP4 and FABP5 was performed to study cell proliferation and apoptosis. Mice with Fabp4 and Fabp5 deletion ( Fabp45 -/- ) and wild type (WT) mice were incubated with hypoxia (10% O 2 ) to induced PAH. Egln1 Tie2Cre mice were bred with Fabp45 -/- mice to generate Egln1 Tie2Cre / Fabp45 -/- mice. Results: We identified five distinct EC subpopulations in both WT and Egln1 Tie2Cre mice via scRNA-seq. Unexpectedly, the number of Cluster (EC2, 49.8%) was markedly increased in Egln1 Tie2Cre lung compared with WT lung (2.8%). EC2 cluster (mainly from Egln1 Tie2Cre lung) was characterized by little expression of Tmem100 , Cldn5 , Tspan7 , Calcrl and Foxf1 and high expression of Fabp4, Cdh13, Sparl1 and Fabp5 . Fatty acid-binding protein (FABP) 4 and FABP5 (FABP4-5) were highly induced in PAECs from IPAH patients. Knockdown of FABP4-5 reduced EC proliferation and starvation-induced Caspase 3/7 activity. Fabp45 -/- mice were protected from hypoxia-induced PAH compared to WT mice. Moreover, Egln1 Tie2Cre / Fabp45 -/- mice also exhibited a reduction of RVSP and RV hypertrophy compared to Egln1 Tie2Cre mice. Conclusions: ScRNA-seq analysis identifies a unique endothelial population (FABP4 + TMEM100 - ) highly enriched in the lung of severe PAH mice. Knockdown of FABP4-5 reduces EC proliferation starvation-induced injury. Genetic deletion of FABP4-5 protects from hypoxia and Egln1 deficiency-induced PAH in mice.

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Endothelial Plasticity Drives Arterial Remodeling Within the Endocardium After Myocardial Infarction

Circulation Research ◽

10.1161/circresaha.116.306476 ◽

2015 ◽

Vol 116 (11) ◽

pp. 1765-1771 ◽

Cited By ~ 36

Author(s):

Lucile Miquerol ◽

Jérome Thireau ◽

Patrice Bideaux ◽

Rachel Sturny ◽

Sylvain Richard ◽

...

Keyword(s):

Myocardial Infarction ◽

Arterial Remodeling ◽

Endothelial Plasticity

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Endothelial Plasticity: Shifting Phenotypes through Force Feedback

Stem Cells International ◽

10.1155/2016/9762959 ◽

2016 ◽

Vol 2016 ◽

pp. 1-15 ◽

Cited By ~ 28

Author(s):

Guido Krenning ◽

Valerio G. Barauna ◽

José E. Krieger ◽

Martin C. Harmsen ◽

Jan-Renier A. J. Moonen

Keyword(s):

Endothelial Cells ◽

Shear Stress ◽

Force Feedback ◽

Fluid Shear Stress ◽

Cyclic Strain ◽

Endothelial Lining ◽

Mesenchymal Transition ◽

Hemodynamic Forces ◽

Endothelial To Mesenchymal Transition ◽

Endothelial Plasticity

The endothelial lining of the vasculature is exposed to a large variety of biochemical and hemodynamic stimuli with different gradients throughout the vascular network. Adequate adaptation requires endothelial cells to be highly plastic, which is reflected by the remarkable heterogeneity of endothelial cells in tissues and organs. Hemodynamic forces such as fluid shear stress and cyclic strain are strong modulators of the endothelial phenotype and function. Although endothelial plasticity is essential during development and adult physiology, proatherogenic stimuli can induce adverse plasticity which contributes to disease. Endothelial-to-mesenchymal transition (EndMT), the hallmark of endothelial plasticity, was long thought to be restricted to embryonic development but has emerged as a pathologic process in a plethora of diseases. In this perspective we argue how shear stress and cyclic strain can modulate EndMT and discuss how this is reflected in atherosclerosis and pulmonary arterial hypertension.

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New insights into the plasticity of the endothelial phenotype

Biochemical Society Transactions ◽

10.1042/bst20110723 ◽

2011 ◽

Vol 39 (6) ◽

pp. 1639-1643 ◽

Cited By ~ 4

Author(s):

Lindsay S. Cooley ◽

Dylan R. Edwards

Keyword(s):

Endothelial Cell ◽

Embryonic Development ◽

Vascular System ◽

Cell Lineage ◽

Vascular Diseases ◽

Lineage Specification ◽

Cell Lineages ◽

Endothelial Phenotype ◽

Lymphatic Vasculature ◽

Endothelial Plasticity

The mammalian vascular system consists of two distinct, but closely related, networks: the blood vasculature (itself divided into arterial and venous networks) and the lymphatic vasculature. EC (endothelial cell) lineage specification has been proposed to be determined during embryonic development, after which the ECs are committed to their fate. However, increasing evidence suggests that ECs retain various degrees of plasticity, and have the ability to express characteristics of alternative cell lineages. Therapeutic control of endothelial plasticity will allow greater understanding of the genesis and treatment of several vascular diseases.

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Endothelial plasticity in fibrosis and epigenetics as a therapeutic target

10.33612/diss.146265795 ◽

2020 ◽

Author(s):

◽

Melanie Hulshoff

Keyword(s):

Therapeutic Target ◽

Endothelial Plasticity

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Loss of endothelial plasticity as a mechanism for the salt sensitive patient with essential hypertension

International Journal of Cardiology ◽

10.1016/j.ijcard.2009.09.353 ◽

2009 ◽

Vol 137 ◽

pp. S104-S105

Author(s):

R.J. MACGINLEY ◽

A.S. TODD ◽

R.J. WALKER

Keyword(s):

Essential Hypertension ◽

Endothelial Plasticity

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ADAMTS1 Supports Endothelial Plasticity of Glioblastoma Cells with Relevance for Glioma Progression

Biomolecules ◽

10.3390/biom11010044 ◽

2020 ◽

Vol 11 (1) ◽

pp. 44

Author(s):

Orlando Serrano-Garrido ◽

Carlos Peris-Torres ◽

Silvia Redondo-García ◽

Helena G. Asenjo ◽

María del Carmen Plaza-Calonge ◽

...

Keyword(s):

Basic Knowledge ◽

Sequencing Data ◽

Extracellular Proteases ◽

Human Gliomas ◽

Primary Glioblastoma ◽

Current Availability ◽

Massive Sequencing ◽

The Central Nervous System ◽

Endothelial Plasticity ◽

Cell Subpopulations

Gliomas in general and the more advanced glioblastomas (GBM) in particular are the most usual tumors of the central nervous system with poor prognosis. GBM patients develop resistance to distinct therapies, in part due to the existence of tumor cell subpopulations with stem-like properties that participate in trans-differentiation events. Within the complex tumor microenvironment, the involvement of extracellular proteases remains poorly understood. The extracellular protease ADAMTS1 has already been reported to contribute to the plasticity of cancer cells. Accordingly, this basic knowledge and the current availability of massive sequencing data from human gliomas, reinforced the development of this work. We first performed an in silico study of ADAMTS1 and endothelial markers in human gliomas, providing the basis to further assess these molecules in several primary glioblastoma-initiating cells and established GBM cells with the ability to acquire an endothelial-like phenotype. Using a co-culture approach of endothelial and GBM cells, we noticed a relevant function of ADAMTS1 in GBM cells leading the organization of endothelial-like networks and, even more significantly, we found a blockade of the formation of tumor-spheres and a deficient response to hypoxia in the absence of ADAMTS1. Our data support a chief role of this protease modulating the phenotypic plasticity of GBM.

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Cytoskeleton Reorganization in EndMT—The Role in Cancer and Fibrotic Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms222111607 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11607

Author(s):

Wojciech Michał Ciszewski ◽

Marta Ewelina Wawro ◽

Izabela Sacewicz-Hofman ◽

Katarzyna Sobierajska

Keyword(s):

Cell Shape ◽

Current Knowledge ◽

Cell Junctions ◽

Migration And Invasion ◽

Mesenchymal Phenotype ◽

Mesenchymal Transition ◽

Cytoskeleton Reorganization ◽

Fibrotic Diseases ◽

Endothelial Plasticity ◽

Endothelial Mesenchymal Transition

Chronic inflammation promotes endothelial plasticity, leading to the development of several diseases, including fibrosis and cancer in numerous organs. The basis of those processes is a phenomenon called the endothelial–mesenchymal transition (EndMT), which results in the delamination of tightly connected endothelial cells that acquire a mesenchymal phenotype. EndMT-derived cells, known as the myofibroblasts or cancer-associated fibroblasts (CAFs), are characterized by the loss of cell–cell junctions, loss of endothelial markers, and gain in mesenchymal ones. As a result, the endothelium ceases its primary ability to maintain patent and functional capillaries and induce new blood vessels. At the same time, it acquires the migration and invasion potential typical of mesenchymal cells. The observed modulation of cell shape, increasedcell movement, and invasion abilities are connected with cytoskeleton reorganization. This paper focuses on the review of current knowledge about the molecular pathways involved in the modulation of each cytoskeleton element (microfilaments, microtubule, and intermediate filaments) during EndMT and their role as the potential targets for cancer and fibrosis treatment.

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