Next-generation sequencing analysis of Abcg2-expressing vascular endothelial stem cells and mature endothelial cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE123999 | GEO | 2018/12/18
REPOSITORIES: GEO
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Project description:Next-generation sequencing analysis of Abcg2-expressing vascular endothelial stem cells and mature endothelial cells
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Project description:Blood vessels are continually exposed to circulating lipids and elevations of ApoB containing lipoproteins cause atherosclerosis. Lipoprotein metabolism is highly regulated by lipolysis, largely at the level of the capillary endothelium lining metabolically active tissues. How large blood vessels, the site of atherosclerotic vascular disease, regulate the flux of fatty acids (FA) into triglyceride (TG) rich lipid droplets (LD) is not known. Here, we show that deletion of the enzyme, adipose triglyceride lipase (ATGL) in the endothelium, leads to neutral lipid accumulation in vessels and impairs endothelial dependent vascular tone and nitric oxide synthesis to promote endothelial dysfunction. Mechanistically, the loss of ATGL leads to endoplasmic reticulum stress-induced inflammation, thereby promoting EC dysfunction. Consistent with this mechanism, deletion of endothelial ATGL markedly increases lesion size in a model of atherosclerosis. Together, these data demonstrate that the dynamics of FA flux through LD impacts EC homeostasis and consequently large vessel function during normal physiology and in a chronic disease state
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Project description:Blood vessels are continually exposed to circulating lipids and elevations of ApoB containing lipoproteins cause atherosclerosis. Lipoprotein metabolism is highly regulated by lipolysis, largely at the level of the capillary endothelium lining metabolically active tissues. How large blood vessels, the site of atherosclerotic vascular disease, regulate the flux of fatty acids (FA) into triglyceride (TG) rich lipid droplets (LD) is not known. Here, we show that deletion of the enzyme, adipose triglyceride lipase (ATGL) in the endothelium, leads to neutral lipid accumulation in vessels and impairs endothelial dependent vascular tone and nitric oxide synthesis to promote endothelial dysfunction. Mechanistically, the loss of ATGL leads to endoplasmic reticulum stress-induced inflammation, thereby promoting EC dysfunction. Consistent with this mechanism, deletion of endothelial ATGL markedly increases lesion size in a model of atherosclerosis. Together, these data demonstrate that the dynamics of FA flux through LD impacts EC homeostasis and consequently large vessel function during normal physiology and in a chronic disease state
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Project description:Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. AM plays critical roles in blood vessels, including regulation of vascular stability and permeability. To elucidate the autocrine / paracrine function of AM in endothelial cells in vivo. A conditional knockout of AM in endothelial cells (AM EC-KO) was used. The amount of vascularization the matrigel implants was lower in AM EC-KO mice indicating a defective angiogenesis. Moreover, ablation of AM in endothelial cells revealed increased vascular permeability in comparison with wildtype littermates. In addition, AM EC-KO lungs exhibited significantly less tumor growth than littermate WT mice using a syngeneic model of metastasis. Furthermore, following middle cerebral artery permanent occlusion, there was a significant infarct size decrease in animals lacking endothelial AM when compared to their wild type counterparts. AM is an important regulator of EC function, angiogenesis, tumorigenesis and brain response to ischemia. Studies of AM should bring novel approaches to the treatment of vascular diseases. Lung endothelial mRNA profiles of wild type (WT) and adrenomedullin endothelial cell conditional knockout (AM EC-KO) mice were generated by deep sequencing using Illumina GAIIx.
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Project description:The heterogeneity of endothelial cells (ECs), lining blood vessels, across tissues remains incompletely inventoried. We constructed an atlas of >32,000 single-EC transcriptomic data from 11 tissues of the model organism Mus musculus. We propose a new classification of EC phenotypes based on transcriptome signatures and inferred putative biological features. We identified top-ranking markers for ECs from each tissue. ECs from different vascular beds (arteries, capillaries, veins, lymphatics) resembled each other across tissues, but only arterial, venous and lymphatic (not capillary) ECs shared markers, illustrating a greater heterogeneity of capillary ECs. We identified high-endothelial-venule and lacteal-like ECs in the intestines, and angiogenic ECs in healthy tissues. Metabolic transcriptomes of ECs differed amongst spleen, lung, liver, brain and testis, while being similar for kidney, heart, muscle and intestines. Within tissues, metabolic gene expression was heterogeneous amongst ECs from different vascular beds, altogether highlighting large EC heterogeneity.
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Project description:Introduction: Capillary malformation (CM) occurs sporadically and is associated with Sturge-Weber syndrome (SWS). The somatic mosaic mutation in GNAQ (c.548GàA, p.R183Q) is enriched in endothelial cells (EC) in skin CM and SWS brain CM. Our goal was to investigate how the mutant G-protein a-q subunit (Gaq) alters EC signaling and disrupts capillary morphogenesis. Approach and results: We used lentiviral constructs to express p.R183Q or wild-type GNAQ in normal human endothelial colony forming cells (EC-R183Q and EC-WT respectively). EC-R183Q constitutively activated phospholipase-C β3 (PLCβ3), a downstream effector of Gαq. Activated PLCβ3 was also detected in human CM tissue sections. Bulk RNA-seq analyses of mutant versus wild-type EC indicated constitutive activation of protein kinase C (PKC), NF-κB and calcineurin signaling in EC-R183Q. Increased expression of downstream targets in these pathways, Angiopoetin-2 (ANGPT2), C-X-C Motif Chemokine Ligand 5 (CXCL5) and Down Syndrome Critical Region Protein 1.4 (DSCR1.4) were confirmed by qPCR and immunostaining of human CM tissue sections. The Gαq inhibitor YM-254890 reduced mRNA expression levels of these targets in EC-R183Q while the pan-PKC inhibitor AEB071 reduced ANGPT2 and CXCL5 but not DSCR1.4. EC-R183Q formed enlarged blood vessels in mice, reminiscent of those found in human CM, with robust endothelial ANGPT2. Conclusions: Gaq-R183Q, when expressed in ECs, establishes constitutively active PLCb3 signaling that leads to a pro-angiogenic, pro-inflammatory phenotype. EC-R183Q are sufficient to form CM-like vessels in mice which provides the first evidence that endothelial Gaq-R183Q is causative for CM.
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Project description:Autologous endothelial cells are promising alternative angiogenic cell sources in trials of therapeutic vasculogenesis; in the treatment of vascular diseases and in the field of tissue engineering. A population of endothelial cells (ECs) with long-term proliferative capability can be isolated from human peripheral blood. They are called endothelial colony forming cells (ECFCs), and are considered to be an endothelial precursor population. They can be expanded in cell factories to sufficient numbers for clinical applications, but as the number of isolated primary ECs is low, the culture period required may be quite long. Another EC population that is easily available in the autologous setting and may be expanded in vitro through several population doublings are the ECs from adipose tissue (AT-ECs). Through extensive comparisons using whole-genome microarray analysis, morphology, phenotype and functional assays, we wanted to evaluate the potential of these EC populations for use in clinical neovascularization. Global gene expression profiling of ECFCs, AT-ECs and the classical EC population, human umbilical vein ECs showed that the EC populations clustered as unique populations, but very close to each other. By cell surface phenotype and vasculogenic potential in vitro and in vivo we also found the ECFCs to be extremely similar to AT-ECs. These properties, and easy access in the autologous setting, suggest that both AT-ECs and ECFCs may be useful in trials of therapeutic neovascularization. However, AT-ECs may be a more practical alternative for obtaining large quantities of autologous ECs.
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