Non-coding RNAs: key regulators of smooth muscle cell fate in vascular disease.

The vascular smooth muscle cell (SMC) is one of the most plastic cells in the body. Understanding how non-coding RNAs (ncRNAs) regulate SMC cell-fate decision making in the vasculature has significantly enhanced our understanding of disease development, and opened up exciting new avenues for potential therapeutic applications. Recent studies on SMC physiology have in addition challenged our traditional view on their role and contribution to vascular disease, mainly in the setting of atherosclerosis as well as aneurysm disease, and restenosis after angioplasties. The impact of SMC behaviour on vascular disease is now recognized to be context dependent; SMC proliferation and migration can be harmful or beneficial, whereas their apoptosis, senescence, and switching into a more macrophage-like phenotype can promote inflammation and disease progression. This is in particular true for atherosclerosis-related diseases, where proliferation of SMCs was believed to promote lesion formation, but may also prevent plaque rupture by stabilizing the fibrous cap. Based on newer findings of genetic lineage tracing studies, it was revealed that SMC phenotypic switching can result in less-differentiated forms that lack classical SMC markers while exhibiting functions more related to macrophage-like cells. This switching can directly promote atherogenesis. The aim of this current review is to summarize and discuss how ncRNAs (mainly microRNAs and long ncRNAs) are involved in SMC plasticity, and how they directly affect vascular disease development and progression. Finally, we want to critically assess where potential future therapies could be useful to influence the burden of vascular diseases.