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miR‐23b regulates CDK‐activating kinase complex through cyclin H repression to modulate endothelial transcription and growth under flow (696.7)

The flow regulation of microRNAs (miRNAs) in endothelial cells (ECs) plays a significant role in vascular homeostasis and diseases. We used a combination of an in vitro cell perfusion system and in vivo studies on experimental animals to elucidate the molecular mechanism by which the pulsatile shear flow (PS)‐induced miR‐23b exerts anti‐proliferative effects on ECs. Our results demonstrated that PS induces the transcription factor KLF2 to promote miR‐23b biosynthesis; the increase in miR‐23b then represses cyclin H (CCNH) to impair the activity and integrity of CDK‐activating kinase complex (CAK). The inhibitory effect of miR‐23b on CAK further suppresses cell cycle progression via reducing the basal transcription and phosphorylation of CDK2/4. While PS regulates the miR‐23b/CAK pathway to exert anti‐proliferative effects on ECs, oscillatory shear flow (OS) has little effect on the miR‐23b/CAK pathway and does not cause EC growth arrest. Such flow pattern‐dependent phenomena are validated with an in vivo model on rat carotid artery. Local delivery of miR‐23b precursors to rat carotid artery significantly reduces the EC proliferative phenotype induced by flow disturbance. Our findings unveil a novel mechanism by which hemodynamic forces modulate endothelial homeostasis through miR‐23b and demonstrate the potential of developing miR‐23b‐based therapeutics for cardiovascular diseases.