Specific Circular RNA Signature of Endothelial Cells: Potential Implications in Vascular Pathophysiology

International Journal of Molecular Sciences · 8 authors, 3 centres

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TL;DR

This study identifies a unique set of circular RNAs (circRNAs) that are specifically expressed in endothelial cells (ECs), including four circRNAs (circCARD6, circPLXNA2, circCASC15, circEPHB4) common to all EC types tested. These circRNAs show greater cell-type specificity than linear RNAs, suggesting they could serve as superior biomarkers for vascular health and disease. The findings have potential clinical implications for diagnosing and treating vascular pathologies and cancer by targeting these EC-specific circRNAs.

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**Background:** Endothelial cells (ECs) line the inner wall of blood and lymphatic vessels and play critical roles in vascular homeostasis, angiogenesis, and various pathophysiological processes such as atherosclerosis, lymphedema, and cancer metastasis. Circular RNAs (circRNAs) are a class of covalently closed RNA molecules that are stable, cell-type-specific, and can regulate gene expression. While circRNAs have been studied in many cell types, a systematic characterization of circRNA signatures in ECs has been lacking. This study aimed to explore the circRNA expression landscape in different EC types to identify potential new molecular signatures and EC-specific markers.

**Methods:** The researchers analyzed publicly available RNA sequencing data from primary cultures of human endothelial cells: Human Umbilical Vein Endothelial Cells (HUVECs), Human Artery Endothelial Cells (HUAECs), Human Coronary Artery Endothelial Cells (HCAECs), and Human Dermal Lymphatic Endothelial Cells (HDLECs). Non-endothelial controls included Smooth Muscle Cells from Umbilical Artery (SMC-UAs) and Stromal Vascular Fraction from Superficial Adipose Tissue (SAT-SVFs). CircRNAs were identified de novo using the CIRI2 algorithm, which detects backspliced junctions. Only circRNAs with 10 or more reads were included. Expression profiles were compared using Pearson correlation, variance analysis, and Venn diagrams. Validation was performed by RT-qPCR and RNase R treatment for selected circRNAs.

**Key Results:** A total of 4713 distinct circRNAs were identified across all cell types, with 2254 (47.82%) exclusive to a particular cell type. The number of detected circRNAs varied: 207 for HCAECs, 259 for SAT-SVFs, 483 for HUVECs, 706 for HDLECs, 1570 for SMC-UAs, and 2685 for HUAECs. The majority (95.04%) were exonic circRNAs. Circular RNAs represented 19.48% of total transcripts in HUAECs, 6.05% in HDLECs, 4.92% in HUVECs, and 2.96% in HCAECs. The circular-to-linear ratio (CLR) varied significantly between cell types (p < 0.05), with HCAECs showing the highest average CLR (62%) and HDLECs the lowest (14%). Pearson correlation analysis showed that circRNA expression profiles were more distinct between EC types than mRNA profiles; for example, HDLECs had 77% circRNA expression correlation with HUVECs but only 23% for matched linear RNAs. Four circRNAs were common to all ECs and absent from non-ECs: circCARD6, circPLXNA2, circCASC15, and circEPHB4. These are associated with genes involved in endothelial migration and cancer progression. RT-qPCR validated 11 out of 17 selected circRNAs (65% validation), and RNase R treatment confirmed their circular nature.

**Clinical Implications:** This study reveals that circRNAs exhibit a strikingly unique expression profile specific to individual EC types, making them superior to linear RNAs for distinguishing between endothelial cell types. The identification of EC-specific circRNAs, particularly the four common ones (circCARD6, circPLXNA2, circCASC15, circEPHB4), provides potential new biomarkers for vascular health and disease. Because ECs are in direct contact with blood and lymph, and circRNAs are stable and can be secreted in exosomes, these circRNAs could be used for non-invasive diagnosis or monitoring of vascular pathologies, cardiovascular diseases, and cancers. They may also serve as therapeutic targets; for example, circRNAs involved in cancer-related pathways could be targeted to inhibit tumor growth and metastasis. However, further research and validation are needed to establish clinical significance.

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other

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ophthalmology

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AI pipeline

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92% · A

ORIGINAL PAPER

PMC10779679

Specific Circular RNA Signature of Endothelial Cells: Potential Implications in Vascular Pathophysiology

International Journal of Molecular Sciences

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ABSTRACT

Abstract Circular RNAs (circRNAs) are a recently characterized family of gene transcripts forming a covalently closed loop of single-stranded RNA. The extent of their potential for fine-tuning gene expression is still being discovered. Several studies have implicated certain circular RNAs in pathophysiological processes within vascular endothelial cells and cancer cells independently. However, to date, no comparative study of circular RNA expression in different types of endothelial cells has been performed and analysed through the lens of their central role in vascular physiology and pathology. In this work, we analysed publicly available and original RNA sequencing datasets from arterial, veinous, and lymphatic endothelial cells to identify common and distinct circRNA expression profiles. We identified 4713 distinct circRNAs in the compared endothelial cell types, 95% of which originated from exons. Interestingly, the results show that the expression profile of circular RNAs is much more specific to each cell type than linear RNAs, and therefore appears to be more suitable for distinguishing between them. As a result, we have discovered a specific circRNA signature for each given endothelial cell type. Furthermore, we identified a specific endothelial cell circRNA signature that is composed four circRNAs: circCARD6, circPLXNA2, circCASC15 and circEPHB4. These circular RNAs are produced by genes that are related to endothelial cell migration pathways and cancer progression. More detailed studies of their functions could lead to a better understanding of the mechanisms involved in physiological and pathological (lymph)angiogenesis and might open new ways to tackle tumour spread through the vascular system. Keywords: circRNA, endothelial cell, (lymph)angiogenesis, gene signature

CITATION EXPORT

Leïla Halidou Diallo, Jérôme Mariette, Nathalie Laugero et al.. Specific Circular RNA Signature of Endothelial Cells: Potential Implications in Vascular Pathophysiology. International Journal of Molecular Sciences. (2024). https://doi.org/10.3390/ijms25010680

AUTHORS

8 · 3 CENTRES

Leïla Halidou Diallo, Jérôme Mariette, Nathalie Laugero, Christian Touriol, Florent Morfoisse, Anne-Catherine Prats, Barbara Garmy-Susini, Eric Lacazette

1U1297-I2MC, INSERM, University of Toulouse, 1 Avenue Jean Poulhes, BP 84225, 31432 Toulouse, France; [email protected] (L.H.D.); [email protected] (N.L.); [email protected] (F.M.); [email protected] (A.-C.P.); [email protected] (B.G.-S.)
2MIAT, University of Toulouse, INRAE, 31326 Castanet-Tolosan, France; [email protected]
3UMR1037 INSERM, University of Toulouse, 2 Avenue Hubert Curien, 31100 Toulouse, France; [email protected]