Normalization of vascular intussusception is essential for promoting lung regeneration over fibrosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE272372 | GEO | 2025/07/31
REPOSITORIES: GEO
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2016-11-17 | E-MTAB-4842 | biostudies-arrayexpress
Project description:Proliferation of vascular endothelial cells (ECs) is critical for providing sufficient cells lining the neo-vascular lumen after injury. As compared with parenchymal cells, vascular ECs normally do not develop genetic mutation during injury. Therefore, epigenetic changes such as RNA modification in ECs might be essential for modulating vascular regeneration in damaged lungs. N6-methyladenosine (m6A) modification has been shown as a major mammalian internal mRNA modification. However, the roles of RNA modification in the regulation of N6-methyladenosine (m6A) modification remain elusive. Here we examined m6A modification landscape in transcriptome-wide, and find that m6A is dynamically regulated during ECs proliferation after pneumonectomy (PNX). The result showed the number of m6A peaks in lung ECs 7 days post PNX was higher than that in sham group, and m6A-RIP sequencing revealed that the m6A peaks in Foxo1 exon 1 and exon 2 were increased on day 7 by PNX, suggesting that m6A methylation of these two exons in Foxo1 mRNA is increased in regenerating lung ECs after PNX.
2025-07-31 | GSE272678 | GEO
Project description:Background: Endothelial cell (ECs) heterogeneity is an emerging area of research in EC biology. Veins, arteries, and microvascular endothelial cells, termed “vascular-type” heterogeneity in this report, have been shown to have heterogeneity in gene expression and function. In addition to this innate heterogeneity, we hypothesized that different vascular-type ECs would also demonstrate heterogeneity in their response to shear stress. Objectives: We interrogated whether vascular-type ECs would demonstrate variations in transcriptional expression patterns under shear stress. Methods: Human umbilical vein endothelial cells (HUVECs), human pulmonary arterial endothelial cells (HPAECs), and human microvascular endothelial cells (HMVECs) were commercially purchased and subjected to shear stress conditions of 0, 1, 4, and 10 dynes/cm2 of laminar shear stress. After exposure to shear stress, cells were analyzed for cellular alignment and RNA was extracted and evaluated via bulk RNA-sequencing (RNA-seq). Results: All ECs demonstrated significant changes in alignment under shear stress. Shear stress significantly affected the transcriptomes of ECs resulting in differentially expressed genes and pathways; while several genes were differentially expressed across all three vascular-types (44.2%), most differentially expressed genes were limited to 1 or 2 of the vascular-types. Hemostatic and thrombotic genes were found to have differential expression patterns under conditions of shear stress, and VWF demonstrated a pattern of vascular-type heterogeneity in response to shear stress. Conclusions: Shear stress causes changes in cellular alignment and transcriptional patterns in ECs that is dependent upon underlying vascular-type. Therefore, endothelial vascular-type heterogeneity can regulate response to shear stress, especially in hemostatic and thrombotic gene expression.
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Project description:Calciprotein particles (CPPs), assembled as a result of molecular interactions between fetuin-A and nascent calcium phosphate clusters, are indispensable scavengers of excessive Ca2+ and PO43– ions, thus representing an elegant mechanism which regulates mineral homeostasis. Generation of CPPs represents an evolutionary mechanism to prevent blood supersaturation with Ca2+ and PO43– ions (e.g., as a result of bone resorption) and to thwart extraskeletal calcification, a pathological condition which is frequent in patients with chronic kidney disease. It is believed that formation of CPPs accompanied evolution from the appearance of bony fish; the existence of CPPs in more ancient animals remains uncertain. Shortly after emergence, amorphous, spherical, and submicrometer-sized (30-100 nm) primary CPPs (CPP-P) evolve into crystalline, spindle- or needle-shaped, and micrometer-sized (100-300 nm) secondary CPPs (CPP-S). Upon executing their function of aggregating Ca2+ and PO43– ions, CPPs are removed from the circulation by endothelial cells (ECs), monocytes, and liver or spleen macrophages. Internalisation and digestion of CPPs by ECs induce a chain of detrimental events including an increase in cytosolic Ca2+, mitochondrial and endoplasmic reticulum stress, nuclear factor (NF)-κB-mediated transcriptional response and cytokine release, ultimately contributing to the development of pro-inflammatory endothelial activation, chronic low-grade inflammation, and inflammaging. Pathological permeability of dysfunctional endothelium promotes lipid retention and leukocyte extravasation, together contributing to the development of vascular inflammation, proteolytic environment, degradation of basement membrane and internal elastic lamina, and contractile-to-synthetic switch of vascular smooth muscle cells. Such an ensemble of molecular events ultimately induces intimal hyperplasia, vascular remodeling, and atherosclerotic progression. Hence, CPPs act as a double-edged sword which rescues the human body from an acute life-threatening disease (i.e., extraskeletal calcification) at the cost of promoting long-lasting conditions (i.e., endothelial dysfunction and atherosclerosis). Among the several forms of calcium transfer (free Ca2+ ions, colloidal calciprotein monomers, and particulate CPPs), CPPs are the most efficient in delivering calcium stress to ECs because of their deposition and dissolution in lysosomes, followed by a lysosomal membrane permeabilisation and an excessive Ca2+ migration into the cytosol. The molecular pattern of CPP-induced calcium stress within the ECs is well defined and includes elevated expression of cell adhesion molecules (VCAM1, ICAM1, and E-selectin) and endothelial-to-mesenchymal transition transcription factors (SNAI1, SNAI2, TWIST1, and ZEB1) in combination with an endothelial nitric oxide synthase (eNOS) uncoupling. However, our knowledge on extracellular signatures of such endothelial response remains limited to an augmented release of pro-inflammatory cytokines (IL-6, IL-8, MCP-1/CCL2, MIF, CXCL1, and MIP-3α/CCL20) and pro- or anti-thrombotic molecules (serpin E1/PAI-1 and uPAR). As EC-secreted bioactive factors (termed angiokines) control vascular tone, maintain hemostasis, and regulate instructive signaling governing local homeostasis within the most organs, decryption and interpretation of endothelial secretome in physiological and pathological conditions is of utmost importance. Discovery of a circulating biomarkers specific for endothelial dysfunction, which can be measured by a routine enzyme-linked immunosorbent assay, might inform on specific disease states and prompt to the respective pharmacological interventions. Here, we aimed at deciphering the secretome of ECs treated with either CPP-P or CPP-S, employing ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) for the analysis of serum-free cell culture supernatant. For the objective comparison of heterogeneous arterial ECs, we utilised human coronary artery endothelial cells (HCAEC) and human internal thoracic artery endothelial cells (HITAEC) which comprise an innermost lining in atheroprone and atheroresistant blood vessels (coronary artery and internal thoracic artery, respectively).
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2020-06-29 | MTBLS1764 | MetaboLights
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2020-02-13 | E-MTAB-8077 | biostudies-arrayexpress
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