Protective role of endothelial p53 in stress induced vascular malignancy.
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ABSTRACT:
PROVIDER: PRJNA513346 | ENA |
REPOSITORIES: ENA
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Project description:Accumulation of cellular stress induced mutations has a potential risk for oncogenic transformation. Once the damage is sensed by checkpoint pathway, such as p53, the aberrant cells are immediately eliminated from regular cell cycle system in order to protect life-threatening events. Here, we show endothelial cell (EC)-specific p53 deletion causes spontaneous endothelial tumors with severe hemolytic phenotypes in mice as is the case with hemangioma thrombocytopenia syndrome in human. As a result of the lack of genomic protection by p53, aggravated by oxidative and aging stress induces additional mutation in ECs especially in adipose tissue. This vascular-specific genomic unstability dysregulates the expression of critical genes such as cell cycle signaling leading to aggressive angiosarcomas.
2020-01-01 | GSE124760 | GEO
Project description:Cardiovascular disorders, like atherosclerosis and hypertension, are increasingly known to be associated with vascular cognitive impairment (VCI). In particular, intracranial atherosclerosis is one of the main causes of VCI, although plaque development occurs later in time and is structurally different compared to atherosclerosis in extracranial arteries. Recent data suggest that endothelial cells (ECs) that line the intracranial arteries may exert anti-atherosclerotic effects due to yet unidentified pathways. To gain insights into underlying mechanisms, we isolated post-mortem endothelial cells from both the intracranial basilar artery (BA) and the extracranial common carotid artery (CCA) from the same individual (total of 15 individuals) with laser capture microdissection. RNA sequencing revealed a distinct molecular signature of the two endothelial cell populations of which the most prominent ones were validated by means of qPCR. Our data reveal for the first time that intracranial artery ECs exert an immune quiescent phenotype. Secondly, genes known to be involved in the response of ECs to damage (inflammation, differentiation, adhesion, proliferation, permeability and oxidative stress) are differentially expressed in intracranial ECs compared to extracranial ECs. Finally, Desmoplakin (DSP) and Hop Homeobox (HOPX), two genes expressed at a higher level in intracranial ECs, and Sodium Voltage-Gated Channel Beta Subunit 3 (SCN3B), a gene expressed at a lower level in intracranial ECs compared to extracranial ECs, were shown to be responsive to shear stress and/or hypoxia. With our data we present a set of intracranial-specific endothelial genes that may contribute to its protective phenotype, thereby supporting proper perfusion and consequently may preserve cognitive function. Deciphering the molecular regulation of the vascular bed in the brain may lead to the identification of novel potential intervention strategies to halt vascular associated disorders, such as atherosclerosis and vascular cognitive dysfunction.
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Project description:Analysis of p53-deficient (E6-expressing) human vascular smooth muscle cells (VSMCs) that express progerin, a mutated form of lamin A resposible for Hutchinson- Gilford progeria syndrome (HGPS). p53 pathway is associated with HGPS. Results provide insight into molecular mechanisms underlying vascular dysfunction of HGPS caused by other than p53 pathway. The gene expression of VSMCs induced to express E6 and either lamin A or progerin by retroviral vectors.
2013-09-22 | E-GEOD-47553 | biostudies-arrayexpress
Project description:Analysis of p53-deficient (E6-expressing) human vascular smooth muscle cells (VSMCs) that express progerin, a mutated form of lamin A resposible for Hutchinson- Gilford progeria syndrome (HGPS). p53 pathway is associated with HGPS. Results provide insight into molecular mechanisms underlying vascular dysfunction of HGPS caused by other than p53 pathway.
2013-09-22 | GSE47553 | GEO
Project description:Dysfunction of vascular endothelium is characteristic of many aging-related diseases, including Alzheimers disease (AD) and AD-related dementias (ADRD). While it is widely posited that endothelial cell dysfunction contributes to the pathogenesis and/or progression of AD/ADRD, it is not clear how. A plausible hypothesis is that intercellular trafficking of extracellular vesicles (EVs) from senescent vascular endothelial cells promotes vascular endothelial cell dysfunction. To test this hypothesis, we compared the expression of proteins and miRNAs in EVs isolated from early passage (EP) vs. senescent (SEN) primary human coronary artery endothelial cells (HCAECs) from the same donor. Proteomics and miRNA libraries constructed from these EV isolates were evaluated using FunRich gene ontology analysis to compare functional enrichment between EP and SEN endothelial cell EVs (ECEVs). Replicative senescence was associated with altered EV abundance and contents independent of changes in EV size. Unique sets of miRNAs and proteins were differentially expressed in SEN-ECEVs, including molecules related to cell adhesion, barrier integrity, receptor signaling, endothelial-mesenchymal transition and cell senescence. miR-181a-5p was the most upregulated miRNA in SEN-ECEVs, increasing >5-fold. SEN-ECEV proteomes supported involvement in several pro-inflammatory pathways consistent with senescence and the senescence-associated secretory phenotype (SASP). These data indicate that SEN-ECEVs are enriched in bioactive molecules implicated in senescence-associated vascular dysfunction, blood-brain barrier impairment, and AD/ADRD pathology. These observations suggest involvement of SEN-ECEVs in the pathogenesis of vascular dysfunction associated with AD/ADRD.
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