Administration of AGNHW enhances neurogenesis and angiogenesis in a mouse model of experimental cerebral ischemia injury
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ABSTRACT:
PROVIDER: PRJNA978575 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24796717_1.fastq.gz | Fastqsanger.gz | |||
| SRR24796717_2.fastq.gz | Fastqsanger.gz | |||
| SRR24796718_1.fastq.gz | Fastqsanger.gz | |||
| SRR24796718_2.fastq.gz | Fastqsanger.gz | |||
| SRR24796719_1.fastq.gz | Fastqsanger.gz |
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Project description:Ischemic injuries will lead to necrotic tissue damage, and post-ischemia angiogenesis plays critical roles in blood flow restoration and tissue recovery. Recently, several types of small RNAs have been reported to be involved in this process. In this study, we first generated a rat brain ischemic model to investigate the involvement of new types of small RNAs in ischemia. We utilized deep sequencing and bioinformatics analyses to demonstrate that the level of small RNA fragments derived from tRNAs was strikingly up-regulated in the ischemic rat brain. Among these sequences, tRNAVal- and tRNAGly-derived small RNAs account for the most abundant segments. The up-regulation of tRNAVal- and tRNAGly-derived fragments was verified through northern blot and quantitative PCR analyses. The levels of these two fragments also increased in a mouse hindlimb ischemia model and cellular hypoxia model. Importantly, the overexpression of tRNAVal- and tRNAGly-derived fragments in endothelial cells inhibited cell proliferation, migration and tube formation. Our results indicate that tRNA-derived fragments are involved in tissue ischemia, and we demonstrate for the first time that tRNAVal- and tRNAGly-derived fragments inhibit angiogenesis by modulating the function of endothelial cells. Examine small RNAs involved in post-ischemia angiogenesis
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Project description:Metformin improves cognition of aged mice by promoting cerebral angiogenesis and neurogenesis
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Project description:Peripheral artery disease is a severe ischemic vascular pathology without effective pharmacological approaches and improving angiogenesis to recover blood perfusion is a promising therapeutic strategy. Endothelial cells (ECs) are the primary cell type contributing to angiogenesis in response to ischemia. However, the molecular mechanisms regulating ischemia-induced angiogenesis remain elusive. We used a discovery-driven approach to identify elevated Peripheral artery disease is a severe ischemic vascular pathology without effective pharmacological approaches and improving angiogenesis to recover blood perfusion is a promising therapeutic strategy. Endothelial cells (ECs) are the primary cell type contributing to angiogenesis in response to ischemia. However, the molecular mechanisms regulating ischemia-induced angiogenesis remain elusive. We used a discovery-driven approach to identify elevated serine/arginine splicing factor 1 (SRSF1) expression in endothelial cells after ischemia. Proteomic analyses identified endogenous SRSF1 accumulated in ECs of the ischemic muscle and responded to hypoxia. Mice deficient in endothelial SRSF1 exhibited impaired blood flow recovery and impaired new capillary formation following HLI. Importantly, overexpression of SRSF1 enhanced blood flow recovery and angiogenesis after HLI. SRSF1 overexpression facilitated, while SRSF1 knockdown suppressed, the angiogenic function of human ECs. To explore the mechanism the mechanisms contributing to SRSF1-promoted endothelial angiogenesis,we conducted transcriptome RNA-seq searching for downstream molecules and verified it through RNA-pull down and chromatin immunoprecipitation qPCR analysis. We performed enhanced crosslinking and immunoprecipitation (eCLIP)-seq to profile the global SRSF1-binding sites on RNAs in HUVECs. Mechanistically, SRSF1 modulated ATF3 alternative splicing, wherein SRSF1 directly bound to ATF3 pre-mRNA and elevated full-length ATF3 transcript at the expense of truncated ATF3Δzip2 transcript, and in turn, ATF3 directly bound to the KLF2 promoter and suppressed KLF2-S1PR1 signaling, through which mediated the SRSF1-promoted endothelial tube formation and angiogenesis. Additionally, alprostadil, the prostaglandin E1 analog, could activate the SRSF1 signaling to improve endothelial angiogenesis in vitro and in vivo. Our findings identified SRSF1 as a novel regulator of ischemia-induced angiogenesis that enhances endothelial angiogenic functions by regulating the ATF3-KLF2/SIPR1 pathway. These results suggest that modulation of endothelial SRSF1 may represent a promising therapeutic approach for treating ischemic vascular diseases.
2025-10-27 | GSE285519 | GEO
Project description:Peripheral artery disease is a severe ischemic vascular pathology without effective pharmacological approaches and improving angiogenesis to recover blood perfusion is a promising therapeutic strategy. Endothelial cells (ECs) are the primary cell type contributing to angiogenesis in response to ischemia. However, the molecular mechanisms regulating ischemia-induced angiogenesis remain elusive. We used a discovery-driven approach to identify elevated serine/arginine splicing factor 1 (SRSF1) expression in endothelial cells after ischemia. Proteomic analyses identified endogenous SRSF1 accumulated in ECs of the ischemic muscle and responded to hypoxia. Mice deficient in endothelial SRSF1 exhibited impaired blood flow recovery and impaired new capillary formation following HLI. Importantly, overexpression of SRSF1 enhanced blood flow recovery and angiogenesis after HLI. SRSF1 overexpression facilitated, while SRSF1 knockdown suppressed, the angiogenic function of human ECs. To explore the mechanism the mechanisms contributing to SRSF1-promoted endothelial angiogenesis,we conducted transcriptome RNA-seq searching for downstream molecules and verified it through RNA-pull down and chromatin immunoprecipitation qPCR analysis. Mechanistically, SRSF1 modulated ATF3 alternative splicing, wherein SRSF1 directly bound to ATF3 pre-mRNA and elevated full-length ATF3 transcript at the expense of truncated ATF3Δzip2 transcript, and in turn, ATF3 directly bound to the KLF2 promoter and suppressed KLF2-S1PR1 signaling, through which mediated the SRSF1-promoted endothelial tube formation and angiogenesis. Additionally, alprostadil, the prostaglandin E1 analog, could activate the SRSF1 signaling to improve endothelial angiogenesis in vitro and in vivo. Our findings identified SRSF1 as a novel regulator of ischemia-induced angiogenesis that enhances endothelial angiogenic functions by regulating the ATF3-KLF2/SIPR1 pathway. These results suggest that modulation of endothelial SRSF1 may represent a promising therapeutic approach for treating ischemic vascular diseases.
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Project description:Metformin improves cognition of aged mice by promoting cerebral angiogenesis and neurogenesis [hADSCs]
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Project description:Metformin improves cognition of aged mice by promoting cerebral angiogenesis and neurogenesis [blood]
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Project description:Constraint-induced movement therapy after cerebral ischemia stimulates axonal growth by decreasing expression levels of Nogo-A, RhoA, and Rho-associated kinase (ROCK) in the ischemic boundary zone. However, it remains unclear if there are any associations between the Nogo-A/RhoA/ROCK pathway and angiogenesis in adult rat brains in pathological processes such as ischemic stroke. In addition, it has not yet been reported whether constraint-induced movement therapy can promote angiogenesis in stroke in adult rats by overcoming Nogo-A/RhoA/ROCK signaling. Here, a stroke model was established by middle cerebral artery occlusion and reperfusion. Seven days after stroke, the following treatments were initiated and continued for 3 weeks: forced limb use in constraint-induced movement therapy rats (constraint-induced movement therapy group), intraperitoneal infusion of fasudil (a ROCK inhibitor) in fasudil rats (fasudil group), or lateral ventricular injection of NEP1-40 (a specific antagonist of the Nogo-66 receptor) in NEP1-40 rats (NEP1-40 group). Immunohistochemistry and western blot assay results showed that, at 2 weeks after middle cerebral artery occlusion, expression levels of RhoA and ROCK were lower in the ischemic boundary zone in rats treated with NEP1-40 compared with rats treated with ischemia/reperfusion or constraint-induced movement therapy alone. However, at 4 weeks after middle cerebral artery occlusion, expression levels of RhoA and ROCK in the ischemic boundary zone were markedly decreased in the NEP1-40 and constraint-induced movement therapy groups, but there was no difference between these two groups. Compared with the ischemia/reperfusion group, modified neurological severity scores and foot fault scores were lower and time taken to locate the platform was shorter in the constraint-induced movement therapy and fasudil groups at 4 weeks after middle cerebral artery occlusion, especially in the constraint-induced movement therapy group. Immunofluorescent staining demonstrated that fasudil promoted an immune response of nerve-regeneration-related markers (BrdU in combination with CD31 (platelet endothelial cell adhesion molecule), Nestin, doublecortin, NeuN, and glial fibrillary acidic protein) in the subventricular zone and ischemic boundary zone ipsilateral to the infarct. After 3 weeks of constraint-induced movement therapy, the number of regenerated nerve cells was noticeably increased, and was accompanied by an increased immune response of tight junctions (claudin-5), a pericyte marker (α-smooth muscle actin), and vascular endothelial growth factor receptor 2. Taken together, the results demonstrate that, compared with fasudil, constraint-induced movement therapy led to stronger angiogenesis and nerve regeneration ability and better nerve functional recovery at 4 weeks after cerebral ischemia/reperfusion. In addition, constraint-induced movement therapy has the same degree of inhibition of RhoA and ROCK as NEP1-40. Therefore, constraint-induced movement therapy promotes angiogenesis and neurogenesis after cerebral ischemia/reperfusion injury, at least in part by overcoming the Nogo-A/RhoA/ROCK signaling pathway. All protocols were approved by the Institutional Animal Care and Use Committee of China Medical University, China on December 9, 2015 (approval No. 2015PS326K).
| S-EPMC6585549 | biostudies-literature