Circular RNAs increase during vascular cell differentiation and are biomarkers for vascular disease

作者：Bernd H. Northoff, Andreas Herbst, Catharina Wenk, Lena Weindl, Gábor Gäbel, Andre Brezski, Kathi Zarnack, Alina Küpper, Stefanie Dimmeler, Alessandra Moretti, Karl-Ludwig Laugwitz, Stefan Engelhardt, Lars Mäegdefessel, Reinier A. Boon, S. Doppler, Martina Dreßen, Harald Lahm, Rüdiger Lange, Markus Krane, Knut Krohn, Alexander Kohlmaier, Lesca M. Holdt, Daniel Teupser · 发表于：Cardiovascular Research · 年份：2025 · DOI：10.1093/cvr/cvaf013 · 被引用次数：9 · 研究领域：Circular RNAs in diseases、Cancer-related molecular mechanisms research、MicroRNA in disease regulation

AIMS: The role of circular RNAs (circRNAs) and their regulation in health and disease are poorly understood. Here, we systematically investigated the temporally resolved transcriptomic expression of circRNAs during differentiation of human induced pluripotent stem cells (iPSCs) into vascular endothelial cells (ECs) and smooth muscle cells (SMCs) and explored their potential as biomarkers for human vascular disease. METHODS AND RESULTS: Using high-throughput RNA sequencing and a de novo circRNA detection pipeline, we quantified the daily levels of 31 369 circRNAs in a 2-week differentiation trajectory from human stem cells to proliferating mesoderm progenitors to quiescent, differentiated EC and SMC. We detected a significant global increase in RNA circularization, with 397 and 214 circRNAs up-regulated greater than two-fold (adjusted P < 0.05) in mature EC and SMC, compared with undifferentiated progenitor cells. This global increase in circRNAs was associated with up-regulation of host genes and their promoters and a parallel down-regulation of splicing factors. Underlying this switch, the proliferation-regulating transcription factor MYC decreased as vascular cells matured, and inhibition of MYC led to down-regulation of splicing factors such as SRSF1 and SRSF2 and changes in vascular circRNA levels. Examining the identified circRNAs in arterial tissue samples and in peripheral blood mononuclear cells (PBMCs) from patients, we found that circRNA levels decreased in atherosc...