Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1274883 | ENA |
REPOSITORIES: ENA
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Project description:The decline of endothelial autophagy is closely related to vascular senescence and disease, although the molecular mechanisms connecting these outcomes in vascular endothelial cells (VECs) remain unclear. Here, we identify a crucial role for CD44, a multifunctional adhesion molecule, in controlling autophagy and aging in VECs. The CD44 intercellular domain (CD44ICD) negatively regulates autophagy by reducing PIK3R4 and PIK3C3 levels and disrupting STAT3-dependent PtdIns3K complexes. CD44 and its homologue clec-31 are increased in aging vascular endothelium and Caenorhabditis elegans, respectively, suggesting that an age-dependent increase in CD44 induces autophagy decline and aging phenotypes. Accordingly, CD44 knockdown ameliorates age-associated phenotypes in VECs. The endothelium-specific CD44ICD knock-in mouse is shorter-lived, with VECs exhibiting obvious premature aging characteristics associated with decreased basal autophagy. Autophagy activation suppresses the premature aging of human and mouse VECs overexpressing CD44ICD, function conserved in the CD44 homologue clec-31 in C. elegans. Our work describes a mechanism coordinated by CD44 function bridging autophagy decline and aging.
2023-08-30 | GSE236523 | GEO
Project description:Endothelial metabolic reprogramming is essential for vascular growth and critical for organ (re)generation, health and life span. Here, we identify a nuclear oxidative catabolic pathway that links cystine metabolism to endothelial gene regulation and angiogenesis. Endothelial cells preparing to proliferate, increase the translation of the transporter (SLC)7A11 to import cystine, which is further oxidatively catabolized by cystathionine gamma lyase (CSE) within the nuclear compartment. This process, preserved in young but not aged tissues, generates acetyl moieties in a pyruvate dehydrogenase dependent manner and initiates specific histone H3 lysine acetylation, leading to chromatin reorganization. Such changes solidify endothelial cell transcriptional programmes and maintain cell proliferation. Combined deletion of the SLC7A11 and CSE causes embryonic lethality and abrogates vascular growth. While SLC7A11 deficiency triggers compensatory de novo cysteine synthesis from methionine, partially preserving angiogenesis; CSE deletion disrupts nuclear cystine oxidative catabolism, endothelial transcription, and vessel formation. Therapeutically, oral cystine supplementation in models of retinopathy of prematurity, acute myocardial infraction and vascular injury in aging promotes vascular growth and repair. Together, our study highlights the role of cyst(e)ine nuclear oxidative catabolism in robust control of endothelial gene transcription, vessel growth and repair.
2026-04-16 | GSE305822 | GEO
Project description:Endothelial metabolic reprogramming is essential for vascular growth and critical for organ (re)generation, health and life span. Here, we identify a nuclear oxidative catabolic pathway that links cystine metabolism to endothelial gene regulation and angiogenesis. Endothelial cells preparing to proliferate, increase the translation of the transporter (SLC)7A11 to import cystine, which is further oxidatively catabolized by cystathionine gamma lyase (CSE) within the nuclear compartment. This process, preserved in young but not aged tissues, generates acetyl moieties in a pyruvate dehydrogenase dependent manner and initiates specific histone H3 lysine acetylation, leading to chromatin reorganization. Such changes solidify endothelial cell transcriptional programmes and maintain cell proliferation. Combined deletion of the SLC7A11 and CSE causes embryonic lethality and abrogates vascular growth. While SLC7A11 deficiency triggers compensatory de novo cysteine synthesis from methionine, partially preserving angiogenesis; CSE deletion disrupts nuclear cystine oxidative catabolism, endothelial transcription, and vessel formation. Therapeutically, oral cystine supplementation in models of retinopathy of prematurity, acute myocardial infraction and vascular injury in aging promotes vascular growth and repair. Together, our study highlights the role of cyst(e)ine nuclear oxidative catabolism in robust control of endothelial gene transcription, vessel growth and repair.
2026-04-16 | GSE305820 | GEO
Project description:Endothelial metabolic reprogramming is essential for vascular growth and critical for organ (re)generation, health and life span. Here, we identify a nuclear oxidative catabolic pathway that links cystine metabolism to endothelial gene regulation and angiogenesis. Endothelial cells preparing to proliferate, increase the translation of the transporter (SLC)7A11 to import cystine, which is further oxidatively catabolized by cystathionine gamma lyase (CSE) within the nuclear compartment. This process, preserved in young but not aged tissues, generates acetyl moieties in a pyruvate dehydrogenase dependent manner and initiates specific histone H3 lysine acetylation, leading to chromatin reorganization. Such changes solidify endothelial cell transcriptional programmes and maintain cell proliferation. Combined deletion of the SLC7A11 and CSE causes embryonic lethality and abrogates vascular growth. While SLC7A11 deficiency triggers compensatory de novo cysteine synthesis from methionine, partially preserving angiogenesis; CSE deletion disrupts nuclear cystine oxidative catabolism, endothelial transcription, and vessel formation. Therapeutically, oral cystine supplementation in models of retinopathy of prematurity, acute myocardial infraction and vascular injury in aging promotes vascular growth and repair. Together, our study highlights the role of cyst(e)ine nuclear oxidative catabolism in robust control of endothelial gene transcription, vessel growth and repair.
2026-04-16 | GSE305826 | GEO
Project description:Endothelial metabolic reprogramming is essential for vascular growth and critical for organ (re)generation, health and life span. Here, we identify a nuclear oxidative catabolic pathway that links cystine metabolism to endothelial gene regulation and angiogenesis. Endothelial cells preparing to proliferate, increase the translation of the transporter (SLC)7A11 to import cystine, which is further oxidatively catabolized by cystathionine gamma lyase (CSE) within the nuclear compartment. This process, preserved in young but not aged tissues, generates acetyl moieties in a pyruvate dehydrogenase dependent manner and initiates specific histone H3 lysine acetylation, leading to chromatin reorganization. Such changes solidify endothelial cell transcriptional programmes and maintain cell proliferation. Combined deletion of the SLC7A11 and CSE causes embryonic lethality and abrogates vascular growth. While SLC7A11 deficiency triggers compensatory de novo cysteine synthesis from methionine, partially preserving angiogenesis; CSE deletion disrupts nuclear cystine oxidative catabolism, endothelial transcription, and vessel formation. Therapeutically, oral cystine supplementation in models of retinopathy of prematurity, acute myocardial infraction and vascular injury in aging promotes vascular growth and repair. Together, our study highlights the role of cyst(e)ine nuclear oxidative catabolism in robust control of endothelial gene transcription, vessel growth and repair.
2026-04-16 | GSE305824 | GEO
Project description:Endothelial metabolic reprogramming is essential for vascular growth and critical for organ (re)generation, health and life span. Here, we identify a nuclear oxidative catabolic pathway that links cystine metabolism to endothelial gene regulation and angiogenesis. Endothelial cells preparing to proliferate, increase the translation of the transporter (SLC)7A11 to import cystine, which is further oxidatively catabolized by cystathionine gamma lyase (CSE) within the nuclear compartment. This process, preserved in young but not aged tissues, generates acetyl moieties in a pyruvate dehydrogenase dependent manner and initiates specific histone H3 lysine acetylation, leading to chromatin reorganization. Such changes solidify endothelial cell transcriptional programmes and maintain cell proliferation. Combined deletion of the SLC7A11 and CSE causes embryonic lethality and abrogates vascular growth. While SLC7A11 deficiency triggers compensatory de novo cysteine synthesis from methionine, partially preserving angiogenesis; CSE deletion disrupts nuclear cystine oxidative catabolism, endothelial transcription, and vessel formation. Therapeutically, oral cystine supplementation in models of retinopathy of prematurity, acute myocardial infraction and vascular injury in aging promotes vascular growth and repair. Together, our study highlights the role of cyst(e)ine nuclear oxidative catabolism in robust control of endothelial gene transcription, vessel growth and repair.
2026-04-16 | GSE305823 | GEO
Project description:Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, genetic premature aging disorder associated with severe atherosclerosis, often resulting in fatal heart attacks and strokes. Progerin, the mutant protein in HGPS, also is expressed in healthy individuals and may play a role in the development of atherosclerosis during physiologic aging. Here, we provide evidence for a primary involvement of vascular endothelium in the pathogenesis of accelerated atherosclerosis in HGPS. Expression of progerin in cultured human endothelial cells induces a dysfunctional phenotype, manifested by activation of multiple pro-inflammatory, pro-atherogenic genes. In particular, our data implicate endothelial-derived interleukin-1 (IL-1) as a key mediator of a pro-inflammatory vascular phenotype. Endothelial activation also is detectable in a mouse model of HGPS, and appears to be conveyed to neighboring vascular cells via autocrine and paracrine signaling. These new mechanistic insights into the vascular pathobiology of HGPS may have therapeutic implications for this disease. Genome-wide transcriptional profiling was carried out to assess functional phenotypic changes in endothelial cells (EC) as a result of progerin expression. Cultured EC were infected with an adenovirus expressing progerin (Ad-Progerin), and as a control, an adenovirus that did not express any construct (Ad-Null). Experiments were preformed with three different EC cultures.
2010-12-02 | E-GEOD-19270 | biostudies-arrayexpress
Project description:We identify transcription factor BACH1 as a master regulator in vascular cells during aging. BACH1 is upregulated in the aorta of old mice. We find BACH1 is located on open chromatin and BACH1 binds to CDKN1A gene enhancer and activates its transcription in endothelial cells. Finally, BACH1 aggravates endothelial cell senescence under oxidative stress. Thus, these findings demonstrate a crucial regulatory role of BACH1 in vascular aging.
2024-09-15 | GSE185210 | GEO
Project description:Previous studies showed that aging in coronary arteries is associated with pro-inflammatory phenotypic changes and decreased NO bioavailability, which, we hypothesized, promotes vascular disease by inducing endothelial apoptosis. To test this hypothesis we characterized pro-apoptotic alterations in the phenotype of coronary arteries of aged (26 month old) and young (3 month old) F344 rats. DNA fragmentation analysis and TUNEL assay showed that in aged vessels there was a ~4 fold increase in the number of apoptotic endothelial cells. Analysis of the expression of apoptosis-related genes (real-time PCR) showed that in aged coronary arteries there was an increased expression of TNFa, TNFb, caspase 9 and an increased presence of cleaved caspase 3 and caspase 9 (Western blotting), whereas expression of TNFR1 and that of TRADD, Bcl-2, Bcl-X(L), Bid, Bax, caspase 8 and caspase 3 were unchanged. Vascular expression and activity of TNFa convertase enzyme were preserved in aging. We propose that aging-induced up-regulation of TNFa and decreased bioavailability of NO promote endothelial apoptosis in coronary arteries that may lead to the development of endothelial dysfunction and ischemic heart disease in the elderly.
2010-06-05 | E-GEOD-619 | biostudies-arrayexpress
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.
2024-08-23 | MSV000095687 | MassIVE