Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
Keenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON M5B 1T8, Canada.
Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):2401-2406. doi: 10.1073/pnas.1715182115. Epub 2018 Feb 21.
Endothelial cell (EC)-enriched protein coding genes, such as endothelial nitric oxide synthase (eNOS), define quintessential EC-specific physiologic functions. It is not clear whether long noncoding RNAs (lncRNAs) also define cardiovascular cell type-specific phenotypes, especially in the vascular endothelium. Here, we report the existence of a set of EC-enriched lncRNAs and define a role for pliced-ranscript ndothelial-nriched lncRNA (STEEL) in angiogenic potential, macrovascular/microvascular identity, and shear stress responsiveness. STEEL is expressed from the terminus of the HOXD locus and is transcribed antisense to HOXD transcription factors. STEEL RNA increases the number and integrity of de novo perfused microvessels in an in vivo model and augments angiogenesis in vitro. The STEEL RNA is polyadenylated, nuclear enriched, and has microvascular predominance. Functionally, STEEL regulates a number of genes in diverse ECs. Of interest, STEEL up-regulates both eNOS and the transcription factor Kruppel-like factor 2 (KLF2), and is subject to feedback inhibition by both eNOS and shear-augmented KLF2. Mechanistically, STEEL up-regulation of eNOS and KLF2 is transcriptionally mediated, in part, via interaction of chromatin-associated STEEL with the poly-ADP ribosylase, PARP1. For instance, STEEL recruits PARP1 to the KLF2 promoter. This work identifies a role for EC-enriched lncRNAs in the phenotypic adaptation of ECs to both body position and hemodynamic forces and establishes a newer role for lncRNAs in the transcriptional regulation of EC identity.
富含内皮细胞（EC）的蛋白编码基因，如内皮型一氧化氮合酶（eNOS），定义了典型的 EC 特异性生理功能。目前尚不清楚长链非编码 RNA（lncRNA）是否也定义了心血管细胞类型特异性表型，特别是在血管内皮中。在这里，我们报告了一组 EC 富集的 lncRNA 的存在，并定义了拼接转录的内皮丰富 lncRNA（STEEL）在血管生成潜力、大血管/微血管特征和切应力反应性中的作用。STEEL 从 HOXD 基因座的末端表达，并且反义转录 HOXD 转录因子。STEEL RNA 增加了体内模型中新灌注微血管的数量和完整性，并增强了体外血管生成。STEEL RNA 聚腺苷酸化，核富集，并具有微血管优势。功能上，STEEL 调节多种基因在不同的 ECs 中。有趣的是，STEEL 上调 both eNOS 和转录因子 Kruppel-like factor 2（KLF2），并且受到 eNOS 和剪切增强的 KLF2 的反馈抑制。从机制上讲，STEEL 对 eNOS 和 KLF2 的上调是转录介导的，部分原因是与染色质相关的 STEEL 与聚 ADP 核糖酶 PARP1 相互作用。例如，STEEL 将 PARP1 募集到 KLF2 启动子上。这项工作确定了富含内皮细胞的 lncRNA 在 EC 对身体位置和血流动力的表型适应中的作用，并确立了 lncRNA 在 EC 特征的转录调控中的新作用。
