In an ageing society more and more people are spending more years living with chronic conditions like atherosclerosis resulting in an enormous health toll. Atherosclerosis, a major cause or morbidity and mortality in our world, is a multifactorial vascular disease driven by endothelial dysfunction.
The vascular endothelium, a monolayer of endothelial cells (ECs), constitutes the inner cellular layer of arteries, veins and capillaries forming a critical interface between blood and tissue. Depending on their location within the circulatory system, vascular ECs may act as sentinel cells sensing microenvironmental cues and as gatekeepers controlling the influx and outflux of circulating molecules, nutrients and immune cells from circulating blood to target tissues and vice versa. This strategic role of ECs makes them as the master regulator of blood-brain and blood-body barrier function, organ-organ and cell-cell crosstalk, immune system activation and organ function in health and disease.
Older people who smoke, have high blood pressure, high glucose or lipid levels in blood and are overweight are at high risk for future cardiovascular events including myocardial infarction and stroke due to endothelial inflammation of the vascular wall leading to atherosclerotic plaque erosion or rupture and subsequently arterial thrombosis. By endothelial inflammation it is meant the EC-triggered activation of the immune system leading to recruitment of circulating immune cells into the vascular wall and development of atherosclerotic plaques. Depending on which arterial bed is affected, atherosclerosis of the coronary arteries leads to acute and chronic coronary syndromes, of the peripheral arteries to peripheral arterial disease and of the cerebrovascular arteries to stroke. All these diseases may lead to organ dysfunction including heart failure, claudication (pain in the legs or arms that occurs while walking or using the arms) and dementia that significantly limit health- and lifespan. Despite recent medical advances and guideline-suggested treatment, atherosclerosis remains an incurable disease. Targeting chronic vascular inflammation seems an obvious solution, but inhibition of one EC signaling pathway is not enough to completely abolish endothelial inflammation due to the presence of aberrant signaling pathways that all lead to an EC pro-inflammatory and pro-atherosclerotic phenotype. Thus, the search for upstream checkpoints of EC immune activation has been the “holy grail” of scientific research in cardiovascular biology and medicine. Understanding the exact molecular mechanisms that orchestrate endothelial cell function and response to environmental stimuli is thus essential for the discovery and development of novel biomarkers and therapeutic strategies in vascular disease.
RNA modifications are (non)reversible, enzymatic ribonucleic acid (RNA) base modifications that expand the RNA alphabet from the 4 canonical nucleotides to more than 170. Among the most abundant RNA modifications in mammals is m6A RNA methylation. RNA modifications may control all aspects of RNA life affecting in a well-coordinated manner several cellular signaling pathways within the same cells. This unique feature of RNA modifications make them ideal upstream coordinators of hundreds of genes involved in several signaling pathways affecting cellular function in health and disease.
Adenosine methylation in the N6 position (m6A) is the most prominent RNA modification in eukaryotes and is mediated by METTL3, METT14 and WTAP writer complex. M6A RNA methylation is a highly conserved RNA modification among organisms and its presence in our cells has been shown to be essential for life. Accumulating recent evidence suggests that m6A RNA methylation controls cellular processes by interfering with the RNA – protein interaction and, thus, RNA fate. The ERC project MODVASC – endothelial RNA modifications in vascular health and disease- aimed at answering the following scientific questions: Is m6A RNA methylation important for EC function in health and disease? Does m6A RNA methylation affect EC gene expression and cellular signaling in response to pro-inflammatory stimuli? How does m6A RNA methylation control RNA fate? Are m6A RNA methylation levels altered in patients with human atherosclerosis? Which genes are differentially methylated in vascular disease?
