Functions and application of circRNAs in vascular aging and aging-related vascular diseases

Figures

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  Fig. 1. Mechanisms of vascular aging. The pathology of vascular aging involving the intricate interplay of multiple factors, such as oxidative stress, mitochondrial dysfunction, cellular senescence, chronic inflammation, vascular wall microenvironment dysfunction, epigenetic alterations, and genomic instability, etc. These interrelated factors together lead to the development of vascular aging. (Created with BioRender.com). ROS, reactive oxygen species; RNS, reactive nitrogen species; EndMT, endothelial-mesenchymal transition

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  Fig. 2. History and characteristics of circRNAs. A Milestones in the discovery and study of circRNAs in vascular diseases. B Biogenesis and functions of circRNAs. Four different models of circRNA biogenesis have been presented: (i) intron-pairing-driven circularization promotes circRNAs biogenesis; (ii) RBP-driven circularization leads to the formation of circRNAs; (iii) exon-skipping generates EIcircRNAs and EcircRNAs; (iv) intron lariat-driven circularization forms CiRNAs. CircRNAs localized primarily in the nucleus can function as transcription regulators, while other circRNAs localized mainly in the cytoplasm act as translation templates and miRNA sponges, interact with RNA-binding proteins, as well as serve as molecule scaffolds. (Created with BioRender.com). CircRNAs, circular RNAs; MiRNA, microRNA; ECs, endothelial cells; VSMCs, vascular smooth muscle cells; RBP, RNA binding protein; EcircRNAs, exon circRNAs; EIciRNAs, exon–intron circRNAs; CiRNAs, circular intronic RNAs

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  Fig. 3. Roles of circRNAs in the physiological and pathological processes of ECs. CircRNAs participate in the occurrence and progression of vascular diseases by regulating physiological and pathological processes in ECs, including proliferation, differentiation, apoptosis, migration, and inflammation. (Created with BioRender.com). Abbreviations: CircRNAs, circular RNAs; ECs, endothelial cells; VCAM1, vascular cell adhesion molecule 1; NFKB1, nuclear factor kappa B subunit 1; HDAC1, class IIa histone deacetylase 1; CCND2, cyclin D2; PLK2, polo-like kinase 2; CDK4, cyclin dependent kinase 4; IFIT1, interferon induced protein with tetratricopeptide repeats 1; HDAC9, class IIa histone deacetylase 9; VEGF, vascular endothelial growth factor; MEOX2, mesenchyme homeobox 2; WNT4, wingless type MMTV integration site family, member 4; NRP1, neuropilin 1; SAV1, salvador family WW domain-containing protein 1 gene; YAP1, yes-associated protein 1

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  Fig. 4. Roles of circRNAs in the physiological and pathological processes of VSMCs. CircRNAs are closely linked to various aspects of VSMC senescence, apoptosis, proliferation, migration, calcification, and phenotypic switching, thereby playing a regulatory role in VSMC aging. (Created with BioRender.com). Abbreviations: CircRNAs, circular RNAs; VSMCs, vascular smooth muscle cells; Kras, kirsten rat sarcoma viral oncogene; THAP1, THAP domain-containing, apoptosis-associated protein 1; CKAP4, cytoskeleton-associated protein 4; NRG-1, neuregulin-1; CDK4, cyclin-dependent kinase 4; ILF3, interleukin enhancer-binding factor 3; FGF-2, fibroblast growth factor 2; CDC20B, cell division cycle 20B; FOXO1, forkhead box protein O1; CCND1, cyclin D1; FUS, fused in sarcoma; SIRT1, sirtuin 1; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; MFN2, mitofusin2; TRIB3, tribbles pseudokinase 3; CAMK2D, calcium/calmodulin dependent protein kinase II delta; CNN3, calponin 3; TET2, tet methylcytosine dioxygenase 2; PCBP1, poly (C)-binding protein 1; ABCC6, ATP-binding cassette subfamily C member 6

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  Fig. 5. CircRNAs in the crosstalk between ECs and VSMCs. A The cZFP609 derived from VSMCs could be transported to ECs via Exos to reduce endothelial angiogenic capacity, mechanically suppressing the expression of VEGFA and inhibiting the nuclear translocation of HIF1α in response to hypoxia. B The exosomal hsa_circ_0008362 secreted by high glucose-induced ECs promotes VSMC calcification by up-regulating Runx2 expression via miR-1251-5p sponging, as well as directly interacting with Runx2 protein to exacerbate VSMC calcification. (Created with BioRender.com). CircRNAs, circular RNAs; ECs, endothelial cells; VSMCs, vascular smooth muscle cells; Exos, exosome; VEGFA, vascular endothelial growth factor-A; ECs, endothelial cells; Runx2, Runt-related transcription factor 2

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  Fig. 6. Effects of up-regulated or down-regulated circRNA expression on aging-related vascular diseases (Created with BioRender.com). CircRNAs, circular RNAs

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  Fig. 7. The clinical application of circRNAs in aging-related vascular diseases. CircRNAs are extracted from samples such as tissues or body fluids, and subsequently identified and quantified using various detection techniques, including RNA sequencing, qRT-PCR, and microarrays, thereby laying the groundwork for understanding the role of circRNAs in vascular aging. In vitro studies use cell culture models to investigate the functional effects of circRNAs, while in vivo studies assess the long-term effects of circRNAs on tissues like blood vessels using animal models. Moreover, preclinical research serves as a crucial bridge between basic studies and clinical applications. By employing these detection and investigation methods, specific circRNAs can be identified and explored as potential biomarkers and/or therapeutic targets. (Created with BioRender.com). Abbreviations: CircRNAs, circular RNAs