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Nature Reviews. Cardiology Jan 2023Endothelial cells are located at the crucial interface between circulating blood and semi-solid tissues and have many important roles in maintaining systemic... (Review)
Review
Endothelial cells are located at the crucial interface between circulating blood and semi-solid tissues and have many important roles in maintaining systemic physiological function. The vascular endothelium is particularly susceptible to pathogenic stimuli that activate tumour suppressor pathways leading to cellular senescence. We now understand that senescent endothelial cells are highly active, secretory and pro-inflammatory, and have an aberrant morphological phenotype. Moreover, endothelial senescence has been identified as an important contributor to various cardiovascular and metabolic diseases. In this Review, we discuss the consequences of endothelial cell exposure to damaging stimuli (haemodynamic forces and circulating and endothelial-derived factors) and the cellular and molecular mechanisms that induce endothelial cell senescence. We also discuss how endothelial cell senescence causes arterial dysfunction and contributes to clinical cardiovascular diseases and metabolic disorders. Finally, we summarize the latest evidence on the effect of eliminating senescent endothelial cells (senolysis) and identify important remaining questions to be addressed in future studies.
Topics: Humans; Endothelial Cells; Cellular Senescence; Endothelium, Vascular; Cardiovascular Diseases
PubMed: 35853997
DOI: 10.1038/s41569-022-00739-0 -
Nature Reviews. Cardiology Mar 2023Vascular endothelial cells form the inner layer of blood vessels where they have a key role in the development and maintenance of the functional circulatory system and... (Review)
Review
Vascular endothelial cells form the inner layer of blood vessels where they have a key role in the development and maintenance of the functional circulatory system and provide paracrine support to surrounding non-vascular cells. Technical advances in the past 5 years in single-cell genomics and in in vivo genetic labelling have facilitated greater insights into endothelial cell development, plasticity and heterogeneity. These advances have also contributed to a new understanding of the timing of endothelial cell subtype differentiation and its relationship to the cell cycle. Identification of novel tissue-specific gene expression patterns in endothelial cells has led to the discovery of crucial signalling pathways and new interactions with other cell types that have key roles in both tissue maintenance and disease pathology. In this Review, we describe the latest findings in vascular endothelial cell development and diversity, which are often supported by large-scale, single-cell studies, and discuss the implications of these findings for vascular medicine. In addition, we highlight how techniques such as single-cell multimodal omics, which have become increasingly sophisticated over the past 2 years, are being utilized to study normal vascular physiology as well as functional perturbations in disease.
Topics: Humans; Endothelial Cells; Cell Differentiation; Signal Transduction
PubMed: 36198871
DOI: 10.1038/s41569-022-00770-1 -
Cell Feb 2020The heterogeneity of endothelial cells (ECs) across tissues remains incompletely inventoried. We constructed an atlas of >32,000 single-EC transcriptomes from 11 mouse...
The heterogeneity of endothelial cells (ECs) across tissues remains incompletely inventoried. We constructed an atlas of >32,000 single-EC transcriptomes from 11 mouse tissues and identified 78 EC subclusters, including Aqp7 intestinal capillaries and angiogenic ECs in healthy tissues. ECs from brain/testis, liver/spleen, small intestine/colon, and skeletal muscle/heart pairwise expressed partially overlapping marker genes. Arterial, venous, and lymphatic ECs shared more markers in more tissues than did heterogeneous capillary ECs. ECs from different vascular beds (arteries, capillaries, veins, lymphatics) exhibited transcriptome similarity across tissues, but the tissue (rather than the vessel) type contributed to the EC heterogeneity. Metabolic transcriptome analysis revealed a similar tissue-grouping phenomenon of ECs and heterogeneous metabolic gene signatures in ECs between tissues and between vascular beds within a single tissue in a tissue-type-dependent pattern. The EC atlas taxonomy enabled identification of EC subclusters in public scRNA-seq datasets and provides a powerful discovery tool and resource value.
Topics: Animals; Brain; Cardiovascular System; Endothelial Cells; Gastrointestinal Tract; Male; Mice; Mice, Inbred C57BL; Muscles; Organ Specificity; RNA-Seq; Single-Cell Analysis; Testis; Transcriptome
PubMed: 32059779
DOI: 10.1016/j.cell.2020.01.015 -
Cell Metabolism Apr 2020Endothelial cell (EC) metabolism is an emerging target for anti-angiogenic therapy in tumor angiogenesis and choroidal neovascularization (CNV), but little is known...
Endothelial cell (EC) metabolism is an emerging target for anti-angiogenic therapy in tumor angiogenesis and choroidal neovascularization (CNV), but little is known about individual EC metabolic transcriptomes. By single-cell RNA sequencing 28,337 murine choroidal ECs (CECs) and sprouting CNV-ECs, we constructed a taxonomy to characterize their heterogeneity. Comparison with murine lung tumor ECs (TECs) revealed congruent marker gene expression by distinct EC phenotypes across tissues and diseases, suggesting similar angiogenic mechanisms. Trajectory inference predicted that differentiation of venous to angiogenic ECs was accompanied by metabolic transcriptome plasticity. ECs displayed metabolic transcriptome heterogeneity during cell-cycle progression and in quiescence. Hypothesizing that conserved genes are important, we used an integrated analysis, based on congruent transcriptome analysis, CEC-tailored genome-scale metabolic modeling, and gene expression meta-analysis in cross-species datasets, followed by in vitro and in vivo validation, to identify SQLE and ALDH18A1 as previously unknown metabolic angiogenic targets.
Topics: Animals; Endothelial Cells; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Lung Neoplasms; Macular Degeneration; Male; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Sequence Analysis, RNA; Single-Cell Analysis; Transcriptome
PubMed: 32268117
DOI: 10.1016/j.cmet.2020.03.009 -
Angiogenesis May 2021There are two vascular networks in mammals that coordinately function as the main supply and drainage systems of the body. The blood vasculature carries oxygen,... (Review)
Review
There are two vascular networks in mammals that coordinately function as the main supply and drainage systems of the body. The blood vasculature carries oxygen, nutrients, circulating cells, and soluble factors to and from every tissue. The lymphatic vasculature maintains interstitial fluid homeostasis, transports hematopoietic cells for immune surveillance, and absorbs fat from the gastrointestinal tract. These vascular systems consist of highly organized networks of specialized vessels including arteries, veins, capillaries, and lymphatic vessels that exhibit different structures and cellular composition enabling distinct functions. All vessels are composed of an inner layer of endothelial cells that are in direct contact with the circulating fluid; therefore, they are the first responders to circulating factors. However, endothelial cells are not homogenous; rather, they are a heterogenous population of specialized cells perfectly designed for the physiological demands of the vessel they constitute. This review provides an overview of the current knowledge of the specification of arterial, venous, capillary, and lymphatic endothelial cell identities during vascular development. We also discuss how the dysregulation of these processes can lead to vascular malformations, and therapeutic approaches that have been developed for their treatment.
Topics: Animals; Blood Vessels; Endothelial Cells; Humans; Lymphatic Vessels; Vascular Malformations
PubMed: 33844116
DOI: 10.1007/s10456-021-09785-7 -
Blood May 2019Neutrophils represent the first line of cellular defense against invading microorganism by rapidly moving across the blood-endothelial cell (EC) barrier and exerting... (Review)
Review
Neutrophils represent the first line of cellular defense against invading microorganism by rapidly moving across the blood-endothelial cell (EC) barrier and exerting effector cell functions. The neutrophil recruitment cascade to inflamed tissues involves elements of neutrophil rolling, firm adhesion, and crawling onto the EC surface before extravasating by breaching the EC barrier. The interaction between neutrophils and ECs occurs via various adhesive modules and is a critical event determining the mode of neutrophil transmigration, either at the EC junction (paracellular) or directly through the EC body (transcellular). Once thought to be a homogenous entity, new evidence clearly points to the plasticity of neutrophil functions. This review will focus on recent advances in our understanding of the mechanism of the neutrophil transmigration process. It will discuss how neutrophil-EC interactions and the subsequent mode of diapedesis, junctional or nonjunctional, can be context dependent and how this plasticity may be exploited clinically.
Topics: Animals; Cell Adhesion; Cell Communication; Endothelial Cells; Humans; Inflammation; Neutrophils; Transendothelial and Transepithelial Migration
PubMed: 30898863
DOI: 10.1182/blood-2018-12-844605 -
International Journal of Molecular... Oct 2023Endothelial cells (ECs) form the inner linings of blood vessels, and are directly exposed to endogenous hazard signals and metabolites in the circulatory system. The... (Review)
Review
Endothelial cells (ECs) form the inner linings of blood vessels, and are directly exposed to endogenous hazard signals and metabolites in the circulatory system. The senescence and death of ECs are not only adverse outcomes, but also causal contributors to endothelial dysfunction, an early risk marker of atherosclerosis. The pathophysiological process of EC senescence involves both structural and functional changes and has been linked to various factors, including oxidative stress, dysregulated cell cycle, hyperuricemia, vascular inflammation, and aberrant metabolite sensing and signaling. Multiple forms of EC death have been documented in atherosclerosis, including autophagic cell death, apoptosis, pyroptosis, NETosis, necroptosis, and ferroptosis. Despite this, the molecular mechanisms underlying EC senescence or death in atherogenesis are not fully understood. To provide a comprehensive update on the subject, this review examines the historic and latest findings on the molecular mechanisms and functional alterations associated with EC senescence and death in different stages of atherosclerosis.
Topics: Humans; Endothelial Cells; Cellular Senescence; Atherosclerosis; Oxidative Stress; Signal Transduction
PubMed: 37894840
DOI: 10.3390/ijms242015160 -
Nature Sep 2018Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. It is expressed by endothelial cells, but surprisingly...
Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. It is expressed by endothelial cells, but surprisingly shows negligible glutamine-synthesizing activity in these cells at physiological glutamine levels. Here we show in mice that genetic deletion of Glul in endothelial cells impairs vessel sprouting during vascular development, whereas pharmacological blockade of glutamine synthetase suppresses angiogenesis in ocular and inflammatory skin disease while only minimally affecting healthy adult quiescent endothelial cells. This relies on the inhibition of endothelial cell migration but not proliferation. Mechanistically we show that in human umbilical vein endothelial cells GLUL knockdown reduces membrane localization and activation of the GTPase RHOJ while activating other Rho GTPases and Rho kinase, thereby inducing actin stress fibres and impeding endothelial cell motility. Inhibition of Rho kinase rescues the defect in endothelial cell migration that is induced by GLUL knockdown. Notably, glutamine synthetase palmitoylates itself and interacts with RHOJ to sustain RHOJ palmitoylation, membrane localization and activation. These findings reveal that, in addition to the known formation of glutamine, the enzyme glutamine synthetase shows unknown activity in endothelial cell migration during pathological angiogenesis through RHOJ palmitoylation.
Topics: Actins; Animals; Cell Movement; Endothelial Cells; Female; Glutamate-Ammonia Ligase; Glutamine; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Lipoylation; Mice; Neovascularization, Pathologic; Palmitic Acid; Protein Processing, Post-Translational; Stress Fibers; rho GTP-Binding Proteins; rho-Associated Kinases
PubMed: 30158707
DOI: 10.1038/s41586-018-0466-7 -
Journal of Visualized Experiments : JoVE Sep 2014Angiogenesis is a vital process for normal tissue development and wound healing, but is also associated with a variety of pathological conditions. Using this protocol,...
Angiogenesis is a vital process for normal tissue development and wound healing, but is also associated with a variety of pathological conditions. Using this protocol, angiogenesis may be measured in vitro in a fast, quantifiable manner. Primary or immortalized endothelial cells are mixed with conditioned media and plated on basement membrane matrix. The endothelial cells form capillary like structures in response to angiogenic signals found in conditioned media. The tube formation occurs quickly with endothelial cells beginning to align themselves within 1 hr and lumen-containing tubules beginning to appear within 2 hr. Tubes can be visualized using a phase contrast inverted microscope, or the cells can be treated with calcein AM prior to the assay and tubes visualized through fluorescence or confocal microscopy. The number of branch sites/nodes, loops/meshes, or number or length of tubes formed can be easily quantified as a measure of in vitro angiogenesis. In summary, this assay can be used to identify genes and pathways that are involved in the promotion or inhibition of angiogenesis in a rapid, reproducible, and quantitative manner.
Topics: Animals; Cell Line; Cell Line, Transformed; Culture Media, Conditioned; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Humans; Mice; Neovascularization, Physiologic
PubMed: 25225985
DOI: 10.3791/51312 -
Bioengineered Dec 2021The role of autophagic mechanisms in the protective effect of berberine (BBR) on lipopolysaccharide (LPS)-induced injury in the endothelial cells human umbilical vein...
The role of autophagic mechanisms in the protective effect of berberine (BBR) on lipopolysaccharide (LPS)-induced injury in the endothelial cells human umbilical vein endothelial cells (HUVECs) and human pulmonary microvascular endothelial cells (HPMECs) was investigated. Cell viability, proliferation, and apoptosis were detected by the CCK-8 assay, the EdU kit, and flow cytometry, respectively, and autophagy-related protein expression, the number of autophagic vacuoles, and LC3 double-fluorescence were examined using western blot analysis, transmission electron microscopy, and confocal microscopy, respectively. LPS resulted in a decrease in the cell viability and proliferation of HUVECs and HPMECs and an increase in the number of apoptotic cells, while BBR treatment resulted in an increase in cell viability and proliferation, as well as a decrease in cell apoptosis. Furthermore, BBR could inhibit LPS-induced autophagy, as demonstrated by its inhibitory effects on the LC3-II/LC3-I ratio and Beclin-1 levels and its promotive effect on p62 expression. Addition of the autophagy inducer rapamycin (RAPA) aggravated LPS-induced injury, while treatment with the autophagy blocker 3-methyladenine (3-MA) attenuated the injury. Further, the protective effect of BBR was inhibited by rapamycin. JNK inhibition by SP600125 inhibited LPS-induced autophagy, and BBR could not alter the LPS-induced autophagy in HUVECs and HPMECs that were pretreated with SP600125. The present data indicate that BBR attenuated LPS-induced cell apoptosis by blocking JNK-mediated autophagy in HUVECs and HPMECs. Therefore, the JNK-mediated autophagy pathway could be a potential target for the prevention and treatment of cardiovascular disease.
Topics: Adenine; Anthracenes; Autophagy; Berberine; Cell Proliferation; Cell Survival; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Humans; Lipopolysaccharides; MAP Kinase Signaling System; Protective Agents; Sirolimus
PubMed: 33896366
DOI: 10.1080/21655979.2021.1915671