Endothelial microRNA tells smooth muscle cells to proliferate.

S ince their discovery in the 1990s, many microRNAs (miRs) have been found to control key cellular processes, many of which are relevant to the cardiovascular system. 1 miRs regulate the expression of extensive networks of genes by binding to mRNA molecules in the cytoplasm to inhibit their expression. Therefore, it was quite a surprise when miRs were found in the blood or in the supernatant of cultured cells at relatively stable levels. 2 These discoveries led to a vast amount of reports showing that circulating miRs can act as potential biomarkers for virtually all diseases, including cardiovascular disease. It also was soon discovered that extracellular miRs are not mere waste material but constitute an intercellular communication mechanism. 3 Circulating miRs have been found inside protein complexes, high-density lipoprotein, low-density lipoprotein, and extracellular vesicles like shedding vesicles, exosomes, and apoptotic bodies, which not only prevent RNases from degrading the miRs but also may mediate delivery of the miRs to specific cell types. 4 Intercellular communication through miRs secreted by endothelial cells in extracellular vesicles was recently shown to contribute to atheroprotective mechanisms. Zhou et al 7 show in this issue of Circulation Research that miR-126 is secreted by endothelial cells in protein complexes on atheroprone stimuli. This miR is then taken-up by smooth muscle cells, where it inhibits the expression of proteins that normally keep the cells in a contractile and quiescent state (Figure). In previous studies, secreted miR-126 was implicated in atheroprotection when taken-up by endothelial cells, 6 but the current study suggests that when miR-126 enters smooth muscle cells, atherosclerosis is enhanced. One important aspect of the current study by the Chien laboratory 7 is that miR-126 is not secreted in vesicles, but rather in complex with argonaute proteins and likely other proteins, too. It is not clear how these miR-containing protein complexes are secreted by endothelial cells and how they enter smooth muscle cells, but these questions deserve further study. An interesting finding of the study by Zhou et al 7 is that miR-126 is not transcriptionally regulated by laminar flow, which is consistent with the literature about mammalian miR-126. In fact, miR-126 levels do not alter at all in endothelial cells, despite convincing evidence that miR-126 is secreted under athero-prone conditions. These observations suggest that only a small fraction of endothelial miR-126 is secreted. However, when one takes into account that miR-126 is highly expressed in …