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New insights into circRNA and its mechanisms in angiogenesis regulation in ischemic stroke: a biomarker and therapeutic target

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Abstract

Ischemic stroke accounts for about 71% of strokes worldwide. Due to limited recommended therapeutics for ischemic stroke, more attention is focused on angiogenesis in ischemic stroke. Not long after ischemic stroke, angiogenesis arises and is vital for the prognosis. Various pro-angiogenic, anti-angiogenic factors and their downstream pathways engage in angiogenesis regulation. CircRNAs are differentially expressed after ischemic stroke. Up to now, circRNAs have been found to exert many functions in regulating apoptosis, autophagy, proliferation, and differentiation of neurons and neural stem cells mainly as miRNAs sponges or proteins decoy. Thus, many circRNAs are considered promising biomarkers or therapeutic targets for ischemic stroke. Besides, circRNAs participate in the modulation of endothelial-mesenchymal transition and blood-brain barrier maintenance. Moreover, circRNAs play significant roles in endothelial dysfunction concerning inflammation responses, apoptosis, proliferation, and migration. They correlate with many angiogenesis-related signaling pathways and genes via the circRNA/miRNA/mRNA network. Novel insights into circRNAs significance in angiogenesis regulation in ischemic stroke could be provided for further researches on the clinical application of circRNAs in ischemic stroke.

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Data Availability

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Abbreviations

IS:

Ischemic stroke

VECs:

Vascular endothelial cells

MMPs:

Matrix metalloproteinases

FGF:

Fibroblast growth factors

TIMP:

Tissue inhibitor of matrix metalloproteinase

GPCRs:

G protein-coupled receptors

CSF:

Granulocyte colony-stimulating factor

BBB:

Blood-brain barrier

ICSs:

Intronic complementary sequences

RBPs:

RNA binding proteins

EcircRNAs:

Exonic circular RNAs

CiRNAs:

Intronic circular RNAs

EIciRNAs:

Exon–intron circular RNAs

MBL/MBNL1:

Muscleblind

SEP3:

SEPALLATA3

SRSF1:

Serine/Arginine rich splicing factor 1

m6A:

N6-Methyladenosine

IRESs:

Internal ribosome entry sites

MIRESs m6A:

Induced ribosome engagement sites

BMECs:

Brain microvascular endothelial cells

HBMECs:

Human brain microvascular endothelial cells

OGD/R :

Oxygen-glucose deprivation/reperfusion 

HUVEC:

Human umbilical vein endothelial cell

KEGG:

Kyoto Encyclopedia of Genes and Genomes

DE:

Differentially expressed

DLK1:

Delta-like 1

ATG5:

Autophagy-related 5

TJPs:

Tight junction proteins

EndoMT:

Endothelial-mesenchymal transition

DNMT1:

DNA methyltransferase 1

SOCS3:

Suppressor of cytokine signaling 3

JNK:

c-Jun N terminal kinase;

STAT3:

Signal transducer and activator of transcription 3

NF-kβ:

Nuclear factor kappa-B

HECTD1:

HECT domain E3 ubiquitin protein ligase 1

TRAF3:

Tumor necrosis factor receptor-associated factor 3

VEZF1:

Vascular endothelial zinc finger 1

SOD2:

Superoxide dismutase 2

NR4A1:

Nuclear receptor subfamily 4 group A member 1

PTEN:

Phosphatase and tensin homolog deleted on chromosome ten

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Funding

This This work was funded by the Project Program of National Clinical Research Center for Geriatric Disorders (Xiangya Hospital, Grant No. 2020LNJJ16), the Provincial Key Plan for Research and Development of Hunan (Grant No. 2020SK2067; No. 2020SK2069), the Natural Science Foundation of Hunan Province (Grant No. 2021JJ31109; No. 2020JJ4875), and the Fundamental Research Funds for the Central Universities of Central South University [Grant No. 2021zzts1029; No. 2020zzts269].

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  1. Department of Neurology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, P.R. China

    Liuyang Cheng, Zeyu Liu & Jian Xia

  2. Clinical Research Center for Cerebrovascular Disease of Hunan Province, Central South University, Changsha, China

    Jian Xia

  3. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China

    Jian Xia

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  1. Liuyang Cheng
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The authors declare that all data were generated in-house and that no paper mill was used. Jian Xia contributes to conception. Liuyang Cheng made contributions in retrieving literature, collecting information, and writing the manuscript. Zeyu Liu and Jian Xia participate in revising it and give critical intellectual suggestions.

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Cheng, L., Liu, Z. & Xia, J. New insights into circRNA and its mechanisms in angiogenesis regulation in ischemic stroke: a biomarker and therapeutic target. Mol Biol Rep 50, 829–840 (2023). https://doi.org/10.1007/s11033-022-07949-2

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