m6A Modification Mediates Endothelial Cell Responses to Oxidative Stress in Vascular Aging Induced by Low Fluid Shear Stress.

ABSTRACT

N6-methyladenosine (m6A) is one of the most prevalent, abundant, and internal transcriptional modification and plays essential roles in diverse cellular and physiological processes. Low fluid shear stress (FSS) is a key pathological factor for many cardiovascular diseases, which directly forces on the endothelial cells of vessel walls. So far, the alterations and functions of m6A modifications in vascular endothelial cells at the low FSS are still unknown. Herein, we performed the transcriptome-wide m6A modification profiling of HUVECs at different FSS. We found that the m6A modifications were altered earlier and more sensitive than mRNA expressions in response to FSS. The low FSS increased the m6A modifications at CDS region but decreased the m6A modifications at 3' UTR region and regulated both the mRNA expressions and m6A modifications of the m6A regulators, such as the RBM15 and EIF3A. Functional annotations enriched by the hypermethylated and hypomethylated genes at low FSS revealed that the m6A modifications were clustered in the aging-related signaling pathways of mTOR, PI3K-AKT, insulin, and ERRB and in the oxidative stress-related transcriptional factors, such as HIF1A, NFAT5, and NFE2L2. Our study provided a pilot view of m6A modifications in vascular endothelial cells at low FSS and revealed that the m6A modifications driven by low FSS mediated the cellular responses to oxidative stress and cell aging, which suggested that the m6A modifications could be the potential targets for inhibiting vascular aging at pathological low FSS.