Abstract 147: Endothelial Regulation By Enhancer Associated Long Non-coding RNA

Lining the critical interface between circulating blood and vascular wall, endothelial cells (ECs) play vital functions in health and disease. The optimal gene expression in ECs is essential to maintain endothelial homeostasis, and its dysregulation can lead to EC dysfunction, a common mechanism underlying many metabolic and cardiovascular diseases, e.g. diabetes and diabetes-associated vasculopathy. We identified an enhancer-associated long non-coding RNA (lncRNA) that enhances endothelial nitric oxide synthase (eNOS) expression, aka LEENE in ECs. LEENE is suppressed in diabetes conditions in ECs in vitro, in vivo, and in human arteries. Knockout of leene homologue in mouse resulted in impaired microvascular function, evident in a diabetic hindlimb ischemia model. Overexpression of human LEENE RNA in the knockout mice rescued the ischemic recovery, resembling that of wildtype animals at tissue function and transcriptome, and single cell gene expression levels. Mechanistically, LEENE binds to the promoters of a set of pro-angiogenic genes to induce their transcription, as revealed by chromatin isolation with RNA pulldown combined with sequencing. Taken together, our work demonstrates an essential role for LEENE in the regulation of angiogenesis and tissue perfusion. Functional enhancement of LEENE to restore angiogenesis and blood flow perfusion may provide a novel strategy to tackle ischemic diseases such as peripheral arterial disease.