Angiogenic patterning by STEEL, an endothelial-enriched long noncoding RNA

Area of Science:

• Molecular Biology
• Cardiovascular Research
• Genomics

Background:

• Endothelial cells (ECs) possess specific functions defined by protein-coding genes like eNOS.
• The role of long noncoding RNAs (lncRNAs) in defining cardiovascular cell-specific phenotypes, particularly in vascular endothelium, remains unclear.

Purpose of the Study:

• To identify EC-enriched lncRNAs.
• To define the function of a novel lncRNA, spliced transcript endothelial-enriched lncRNA (STEEL), in EC biology.
• To investigate STEEL's role in angiogenesis, vascular identity, and response to shear stress.

Main Methods:

• Identification and characterization of EC-enriched lncRNAs.
• In vivo studies using a mouse model to assess microvessel formation.
• In vitro angiogenesis assays.
• Analysis of STEEL's molecular mechanisms, including gene expression regulation and protein-protein interactions (e.g., with PARP1).

Main Results:

• A set of EC-enriched lncRNAs was identified, including STEEL.
• STEEL enhances the number and integrity of perfused microvessels in vivo and augments angiogenesis in vitro.
• STEEL is nuclear-enriched, polyadenylated, and shows microvascular predominance.
• STEEL up-regulates endothelial nitric oxide synthase (eNOS) and Kruppel-like factor 2 (KLF2) transcriptionally.
• STEEL interacts with PARP1 to regulate KLF2 promoter activity.

Conclusions:

• EC-enriched lncRNAs play a role in phenotypic adaptation of ECs to hemodynamic forces.
• STEEL is a key regulator of EC identity, angiogenesis, and response to shear stress.
• This study establishes a novel role for lncRNAs in the transcriptional regulation of endothelial cell phenotypes.