Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies

Pharmacological Reviews, Journal Year: 2021, Volume and Issue: 73(3), P. 924 - 967

Published: June 4, 2021

The endothelium, a cellular monolayer lining the blood vessel wall, plays critical role in maintaining multiorgan health and homeostasis. Endothelial functions include dynamic maintenance of vascular tone, angiogenesis, hemostasis, provision an antioxidant, anti-inflammatory, antithrombotic interface. Dysfunction endothelium presents with impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion hyperpermeability, endothelial cell senescence. Recent studies have implicated altered metabolism endothelial-to-mesenchymal transition as new features dysfunction. dysfunction is regarded hallmark many diverse human panvascular diseases, including atherosclerosis, hypertension, diabetes. has also been severe coronavirus disease 2019. Many clinically used pharmacotherapies, ranging from traditional lipid-lowering drugs, antihypertensive antidiabetic drugs to proprotein convertase subtilisin/kexin type 9 inhibitors interleukin 1β monoclonal antibodies, counter part their clinical benefits. regulation by noncoding RNAs provided novel insights into these newly described regulators dysfunction, thus yielding potential therapeutic approaches. Altogether, better understanding versatile (dys)functions cells will not only deepen our comprehension diseases but accelerate effective drug discovery. In this review, we provide timely overview multiple layers function, describe consequences mechanisms identify pathways targeted therapies.

Significance Statement

was initially considered be semipermeable biomechanical barrier gatekeeper health. recent decades, deepened biological led its recognition ubiquitous tissue regulating behavior, innate immunity, cell-cell interactions, wall. cardiovascular, metabolic, emerging infectious diseases. Pharmacotherapies targeting for treatment cardiovascular other

Language: Английский

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Single‐cell RNA sequencing technologies and applications: A brief overview

Clinical and Translational Medicine, Journal Year: 2022, Volume and Issue: 12(3)

Published: March 1, 2022

Language: Английский

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Immunomodulation by endothelial cells — partnering up with the immune system?

Nature reviews. Immunology, Journal Year: 2022, Volume and Issue: 22(9), P. 576 - 588

Published: March 14, 2022

Language: Английский

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Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Jan. 29, 2021

Abstract Endothelial cells play a critical role in the adaptation of tissues to injury. Tissue ischemia induced by infarction leads profound changes endothelial cell functions and can induce transition mesenchymal state. Here we explore kinetics individual cellular responses after myocardial using single RNA sequencing. This study demonstrates time dependent switch proliferation inflammation associated with transient metabolic gene signatures. Trajectory analysis reveals that majority 3 7 days acquire state, characterized expression, which returns baseline 14 Lineage tracing, Cdh5-CreERT2;mT/mG mice followed sequencing, confirms additional hypoxic inflammatory signatures during early late states These data suggest undergo mes-enchymal activation concomitant within first but do not long-term fate. may facilitate migration clonal expansion regenerate vascular network.

Language: Английский

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Pathological angiogenesis: mechanisms and therapeutic strategies

Angiogenesis, Journal Year: 2023, Volume and Issue: 26(3), P. 313 - 347

Published: April 15, 2023

In multicellular organisms, angiogenesis, the formation of new blood vessels from pre-existing ones, is an essential process for growth and development. Different mechanisms such as vasculogenesis, sprouting, intussusceptive, coalescent well vessel co-option, vasculogenic mimicry lymphangiogenesis, underlie vasculature. many pathological conditions, cancer, atherosclerosis, arthritis, psoriasis, endometriosis, obesity SARS-CoV-2(COVID-19), developmental angiogenic processes are recapitulated, but often done so without normal feedback that regulate ordinary spatial temporal patterns formation. Thus, angiogenesis presents challenges yet opportunities design vascular-directed therapies. Here, we provide overview recent insights into development highlight novel therapeutic strategies promote or inhibit to stabilize, reverse, even halt disease progression. our review, will also explore several additional aspects (the switch, hypoxia, angiocrine signals, endothelial plasticity, normalization, cell anergy) operate in parallel canonical speculate how these may be targeted with anti-angiogenic

Language: Английский

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Single-Cell RNA Sequencing Unveils Unique Transcriptomic Signatures of Organ-Specific Endothelial Cells

Circulation, Journal Year: 2020, Volume and Issue: 142(19), P. 1848 - 1862

Published: Sept. 15, 2020

Endothelial cells (ECs) display considerable functional heterogeneity depending on the vessel and tissue in which they are located. Whereas these differences presumably imprinted transcriptome, pathways networks that sustain EC have not been fully delineated.To investigate transcriptomic basis of specificity, we analyzed single-cell RNA sequencing data from tissue-specific mouse ECs generated by Tabula Muris consortium. We used a number bioinformatics tools to uncover markers sources data.We found strong correlation between measurements either or bulk sequencing, thus validating approach. Using graph-based clustering algorithm, certain cluster strongly (eg, liver, brain), whereas others (ie, adipose, heart) overlap with other tissues. identified novel signaling may be involved maintaining their identity. Sex was source endothelial transcriptome discovered Lars2 gene is highly enriched male mice. heart lung mice were conserved human fetal ECs. potential angiocrine interactions cell types analyzing ligand receptor expression patterns.We consortium transcriptional maintain identity identify relationships

Language: Английский

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Biology and therapeutic targeting of vascular endothelial growth factor A

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(11), P. 816 - 834

Published: July 25, 2023

Language: Английский

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Endothelial-to-Mesenchymal Transition in Cancer

Frontiers in Cell and Developmental Biology, Journal Year: 2020, Volume and Issue: 8

Published: Aug. 14, 2020

Cancer is one of the most important causes morbidity and mortality worldwide. Tumor cells grow in a complex microenvironment constituted immune, stromal vascular that supports growth, angiogenesis metastasis. Endothelial are major components microenvironment. These have been described for their plasticity potential to transdifferentiate into mesenchymal through process known as endothelial-to transition (EndMT). This controlled by various factors, which endothelial convert phenotype characterized protein expression motile, contractile morphology. Initially normal heart development, EndMT now identified several pathologies, especially cancer. In this review, we highlight context cancer discuss it an adaptive tumor favors growth dissemination but also resistance treatment. Thus, underline targeting therapeutic strategy.

Language: Английский

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Tumor Endothelial Cells (TECs) as Potential Immune Directors of the Tumor Microenvironment – New Findings and Future Perspectives

Frontiers in Cell and Developmental Biology, Journal Year: 2020, Volume and Issue: 8

Published: Aug. 19, 2020

The tumor microenvironment (TME) plays a central role in cancer development and progression. It represents complex network of cell (sub-)clones variety stromal types. Recently, new technology platforms shed light on the cellular composition TME at very high resolution identified landscape multi-lineage immune cells (e.g. T B lymphocytes, myeloid cells, dendritic cells), associated fibroblasts (CAF) endothelial (TECs). A growing body evidence suggests that metabolically, genetically their transcriptomic profile TECs exhibit unique phenotypic functional characteristics when compared to normal (NECs). Furthermore, is multifaceted as they are not only relevant for promoting angiogenesis but have also evolved key mediators regulation TME. Regulatory mechanisms profoundly impact peripheral trafficking into compartment by acting major gatekeepers transmigration. Moreover, with priming, activation proliferation antigen-presenting themselves. essential formation tertiary lymphoid structures (TLS) within tumor, which recently been treatment response checkpoint antibody therapy. Further NECs proliferative potential well greatly altered gene expression upregulation pro-angiogenic, extracellular matrix remodeling stemness genes), results enhanced secretion immunomodulatory cytokines cell-surface receptors histocompatibility (MHC) checkpoints). TEC phenotype may be rooted an aggressive micro-milieu based stress via hypoxia reactive oxygen species. Vice versa might modulate immunogenicity thereby fostering cancer-associated suppression. This review aims elucidate currently emergent pathophysiological aspects particular focus regulators function main future challenge deeply characterize illuminate ultimate goal identification TEC-specific drug targets improve (immuno-)therapy.

Language: Английский

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A graph neural network model to estimate cell-wise metabolic flux using single-cell RNA-seq data

Genome Research, Journal Year: 2021, Volume and Issue: 31(10), P. 1867 - 1884

Published: July 22, 2021

The metabolic heterogeneity and interplay between cells are known as significant contributors to disease treatment resistance. However, with the lack of a mature high-throughput single-cell metabolomics technology, we yet establish systematic understanding intra-tissue cooperative mechanisms. To mitigate this knowledge gap, developed novel computational method, namely, flux estimation analysis (scFEA), infer cell-wise fluxome from RNA-sequencing (scRNA-seq) data. scFEA is empowered by systematically reconstructed human map factor graph, probabilistic model leverage balance constraints on scRNA-seq data, graph neural network–based optimization solver. intricate information cascade transcriptome metabolome was captured using multilayer networks capitulate nonlinear dependency enzymatic gene expressions reaction rates. We experimentally validated generating an data set matched perturbed oxygen genetic conditions. Application showed consistency predicted observed variation metabolite abundance in also applied five publicly available spatial transcriptomics sets identified context- cell group–specific variations. empowers series downstream analyses including identification modules or groups that share common variations, sensitivity evaluation enzymes regards their impact whole flux, inference cell–tissue cell–cell communications.

Language: Английский

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