The splicing-regulatory lncRNA NTRAS sustains vascular integrity

Area of Science:

• Molecular Biology
• Genetics
• Cardiovascular Biology

Background:

• Vascular integrity is crucial for organ function, preventing edema and inflammation.
• Long non-coding RNAs (lncRNAs) are key gene expression regulators with cell-specific roles.

Purpose of the Study:

• Identify novel endothelial-enriched lncRNAs controlling vascular function.
• Investigate the role of the lncRNA NTRAS in maintaining endothelial cell homeostasis and vascular integrity.

Main Methods:

• Screening for endothelial-specific lncRNAs.
• In vitro silencing of NTRAS in endothelial cells.
• Biochemical analysis of NTRAS-hnRNPL interactions.
• Generation and analysis of Ntras^∆CA/∆CA mutant mice.
• Assessment of vascular permeability, gene splicing, and organ pathology.

Main Results:

• NTRAS was identified as an endothelial-enriched lncRNA regulating endothelial cell function.
• NTRAS silencing led to endothelial dysfunction, increased vascular permeability, and lethality in mice.
• NTRAS sequesters hnRNPL via a CA-dinucleotide repeat motif, controlling TJP1 alternative splicing.
• Deletion of the hnRNPL binding motif in mice repressed TJP1 exon 20 usage, favoring the TJP1α- isoform and increasing endothelial permeability.
• Ntras^∆CA/∆CA mice exhibited reduced retinal vessel growth, heightened vascular permeability, and myocarditis.

Conclusions:

• NTRAS is an essential regulator of vascular integrity.
• The NTRAS-hnRNPL-TJP1 axis is critical for maintaining endothelial barrier function.
• Dysregulation of NTRAS contributes to vascular pathologies.