Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA722495 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Although mitochondrial activity is critical for angiogenesis, its mechanism is not entirely clear. Here, we investigate the angiogenic functions of three separate nuclear genes that encode for mitochondrial proteins, including mitochondrial transcriptional factor (TFAM), respiratory complex IV component (COX10), and a mitochondrial redox protein thioredoxin 2 (TRX2), which are responsible for distinct mitochondrial functions. We aim to investigate if mitochondrial activities regulate common endothelial cell (EC) signaling pathways during angiogenesis. The silencing of Tfam, Cox10, or Trx2 in an in vitro 3D sprouting assay attenuates EC sprouting, which correlated with reduced EC proliferation but not with ROS generation or EC apoptosis. Mice with an inducible deletion of Tfam, Cox10, or Trx2 exhibit retarded retinal vessel growth without penetration into the deep plexi at early ages (P5-P12). The three mutant mice develop arteriovenous malformations (AVM) with microaneurysm formation in the microvessels at advanced ages (P12-P30); the hypovasculature and microaneurysm phenotypes resemble that of aged human retinas and human primitive retinal vascular abnormalities such as Coats’ disease, Leber’s military aneurysms and familial exudative vitreoretinopathy. Single-cell RNA-seq analyses of retinal ECs suggest that the three mutant mice have common EC clusters with reduced gene expressions in anion transporters, actin organization, extracellular matrix, and angiogenesis. These EC clusters also have increased gene expressions in endothelial-mesenchymal transition and arterial markers, correlating with enhanced TGFbR signaling in Tfam, Cox10, or Trx2-deficient mice. Importantly, pharmacological blockade by TGFbR inhibitors attenuated retinal vessel growth retardation and AVM formation in all three mutant mice. Our study demonstrates that mitochondrial dysfunction induces TGF-b receptor-mediated arteriovenous malformations and microaneurysm formation in mouse retinas, and provide a novel model and therapeutic intervention for human primitive retinal vascular abnormalities, which are characterized by retinal vascular malformations and are associated with many pathological complications such as diabetes and hypertension that can result in vision loss.
2022-10-11 | GSE172230 | GEO
Project description:Although mitochondrial activity is critical for angiogenesis, its mechanism is not entirely clear. Here we show that mice with endothelial deficiency of any one of the three nuclear genes encoding for mitochondrial proteins, transcriptional factor (TFAM), respiratory complex IV component (COX10), or redox protein thioredoxin 2 (TRX2), exhibit retarded retinal vessel growth and arteriovenous malformations (AVM). Single-cell RNA-seq analyses indicate that retinal ECs from the three mutant mice have increased TGFβ signaling and altered gene expressions associated with vascular maturation and extracellular matrix, correlating with vascular malformation and increased basement membrane thickening in microvesels of mutant retinas. Mechanistic studies suggest that mitochondrial dysfunction from Tfam, Cox10, or Trx2 depletion induces a mitochondrial localization and MAPKs-mediated phosphorylation of SMAD2, leading to enhanced ALK5-SMAD2 signaling. Importantly, pharmacological blockade of ALK5 signaling or genetic deficiency of SMAD2 prevented retinal vessel growth retardation and AVM in all three mutant mice. Our studies uncover a novel mechanism whereby mitochondrial dysfunction via the ALK5-SMAD2 signaling induces retinal vascular malformations, and have therapeutic values for the alleviation of angiogenesis-associated human retinal diseases.
| S-EPMC9741628 | biostudies-literature
Project description:Spinal arteriovenous malformations (sAVM) were rare and heterogeneous group of blood vessel disorders that affected the function of spinal cord directly or indirectly. In the past decades, the pathogenesis for SAVM was still not elucidated. Here we compared the specimens of four sAVM obtained from surgery and control samples from donations using TMT labeled proteomic study. In our proteomic study, we identified a total of 3101 proteins and 654-proteins were changed in SAVM compares with control, among which 96 proteins were upregulated and 358 proteins were downregulated. Gene Ontology (GO) analysis revealed that extracellular matrix organization in biological process and integrin binding proteins in molecular function were the most enriched items. Four significant changed proteins (PLG, MPZ, MMP9 and RPL23a) were verified by Western blot. The pathway analysis revealed that the changed proteins in pathways of angiogenesis, focal adhesion and cytoplasmic ribosome likely contributed to SAVM. The protein profile changes identified by our proteomic studies provide a comprehensive understanding of sAVM for us.
2018-06-18 | PXD007982 | Pride
Project description:Cerebral arteriovenous malformations (AVMs) are the most common vascular malformations worldwide and the leading cause of hemorrhagic strokes that result in crippling neurological deficits. Here, using newly generated mouse model, we discovered that genome-wide ocuppancy of H4K8ac and H3K27me3 decreased in mouse cerebral AVMs.
2024-05-30 | GSE245171 | GEO
Project description:Object. Detailed and exact mechanisms underlying brain arteriovenous malformations (bAVM) are still confusing in clinic. Understanding the quantitative changes of proteins and signaling pathways would provide useful information for clinicians to understand the formation and development of bAVM and therefore give proper individual treatment strategies. This study was performed to establish a huge human bAVM proteome database by tandem mass tag (TMT)-labeling technique and detect the alteration of proteins and pathways in the development of human bAVM. Methods. This study used quantitative proteomics to profile protein changes with the 6-plex TMT labeling in bAVM lesions. Integrated bioinformatics analysis were used to classify and identify the altered proteins and relating signaling pathways. Western blot analyses were used to identify the reliability of the proteomic data. Results. Our work established one of the largest human bAVM proteome databases to date. A total of 1264 proteins were identified, among which the expression of 316 proteins were changed with 249 proteins upregulated. Bioinformatics analysis revealed a close relevance between cell-cell interactions including focal adhesion, tight junction, gap junction and the development of bAVM. Conclusions. Cell-cell interactions, including focal adhesion, tight junction and gap junction played vital roles in the formation and development of bAVM. Understanding the molecular mechanism underlying bAVM is important for the development of future therapeutic approaches, thereafter making precise and individual treatment strategies in clinic.
2017-01-20 | PXD003289 | Pride
Project description:<p><strong>OBJECTIVE:</strong> This study aimed to investigate the plasma metabolic profile of patients with extracranial arteriovenous malformations (AVM).</p><p><strong>METHOD:</strong> Plasma samples were collected from 32 AVM patients and 30 healthy controls (HC). Ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) was employed to analyze the metabolic profiles of both groups. Metabolic pathway enrichment analysis was performed through Kyoto Encyclopedia of Genes and Genomes (KEGG) database and MetaboAnalyst. Additionally, machine learning algorithms such as Least Absolute Shrinkage and Selection Operator (LASSO) and random forest (RF) were conducted to screen characteristic metabolites. The effectiveness of the serum biomarkers for AVM was evaluated using a receiver-operating characteristics (ROC) curve.</p><p><strong>RESULT:</strong> In total, 184 differential metabolites were screened in this study, with 110 metabolites in positive ion mode and 74 metabolites in negative mode. Lipids and lipid-like molecules were the predominant metabolites detected in both positive and negative ion modes. Several significant metabolic pathways were enriched in AVMs, including lipid metabolism, amino acid metabolism, carbohydrate metabolism and protein translation. Through machine learning algorithms, 9 metabolites were identify as characteristic metabolites, including hydroxy-proline, L-2-Amino-4-methylenepentanedioic acid, piperettine, 20-hydroxy-PGF2a, 2,2,4,4-tetramethyl-6-(1-oxobutyl)-1,3,5-cyclohexanetrione, DL-tryptophan, 9-oxoODE, alpha-Linolenic acid and dihydrojasmonic acid.</p><p><strong>CONCLUSION:</strong> Patients with extracranial AVMs exhibited significantly altered metabolic patterns compared to healthy controls, which could be identified using plasma metabolomics. These findings suggest that metabolomic profiling can aid in the understanding of AVM pathophysiology and potentially inform clinical diagnosis and treatment.</p>
1970-01-01 | MTBLS7753 | MetaboLights
Project description:The overall goal of this project is to investigate the role of TGF-beta signaling in tissue-tissue interactions between myogenic precursors of craniofacial muscles and cranial neural crest cells (CNCCs). Here, we conducted gene expression profiling of the tongue bud from mice at embryonic day E13.5 with a CNCC-specific conditional inactivation of the TGF-beta receptor type 1 gene Alk5. These mice provide a model of microglossia as well as disrupted extraocular and masticatory muscle development, which are congenital birth defects commonly observed in several syndromic conditions. To investigate the adverse effects of dysfunctional TGF-beta signaling on tissue-tissue interactions between CNCCs and myogenic precursors of craniofacial muscles, we analyzed tongue bud tissue of mice with a CNCC-specific conditional inactivation of Alk5 (Wnt1-Cre; Alk5 fl/fl). We performed microarray analyses of the tongue bud of Alk5 fl/fl control mice and Wnt1-Cre; Alk5 fl/fl mutant mice, collected at embryonic day E13.5 (n=4 per group).
2014-06-18 | E-GEOD-52358 | biostudies-arrayexpress
Project description:The overall goal of this project is to investigate the role of TGF-beta signaling in tissue-tissue interactions between myogenic precursors of craniofacial muscles and cranial neural crest cells (CNCCs). Here, we conducted gene expression profiling of the mandibular arch from mice at embryonic day E11.5 with a CNCC-specific conditional inactivation of the TGF-beta receptor type 1 gene Alk5. These mice provide a model of microglossia as well as disrupted extraocular and masticatory muscle development, which are congenital birth defects commonly observed in several syndromic conditions. To investigate the adverse effects of dysfunctional TGF-beta signaling on tissue-tissue interactions between CNCCs and myogenic precursors of craniofacial muscles, we analyzed mandibular arch tissue of mice with a CNCC-specific conditional inactivation of Alk5 (Wnt1-Cre; Alk5 fl/fl). We performed microarray analyses of the mandibular arch of Alk5 fl/fl control mice and Wnt1-Cre; Alk5 fl/fl mutant mice, collected at embryonic day E11.5 (n=4 per group).
2014-06-18 | E-GEOD-52357 | biostudies-arrayexpress
Project description:Object. Detailed and exact mechanisms underlying brain arteriovenous malformations (bAVM) are still confusing in clinic. Understanding the quantitative changes of proteins and signaling pathways would provide useful information for clinicians to understand the formation and development of bAVM and therefore give proper individual treatment strategies. This study was performed to establish a huge human bAVM proteome database by tandem mass tag (TMT)-labeling technique and detect the alteration of proteins and pathways in the development of human bAVM. Methods. This study used quantitative proteomics to profile protein changes with the 6-plex TMT labeling in bAVM lesions. Integrated bioinformatics analysis were used to classify and identify the altered proteins and relating signaling pathways. Western blot analyses were used to identify the reliability of the proteomic data. Results. Our work established one of the largest human bAVM proteome databases to date. A total of 1264 proteins were identified, among which the expression of 316 proteins were changed with 249 proteins upregulated. Bioinformatics analysis revealed a close relevance between cell-cell interactions including focal adhesion, tight junction, gap junction and the development of bAVM. Conclusions. Cell-cell interactions, including focal adhesion, tight junction and gap junction played vital roles in the formation and development of bAVM. Understanding the molecular mechanism underlying bAVM is important for the development of future therapeutic approaches, thereafter making precise and individual treatment strategies in clinic.
2017-03-29 | MSV000080716 | MassIVE