Targeting the 5-HT_1B-YAP positive feedback loop protects against disturbed flow-induced atherogenesis in mice

Atherosclerosis preferentially develops at arterial bifurcations where the endothelial cells are constantly exposed to disturbed flow, and sustained oscillatory shear stress (OSS) triggers endothelial inflammation. The mechanosensitive transcriptional coactivator YAP plays a critical role in disturbed flow-induced endothelial inflammation. Our recent studies show that disturbed flow upregulates the expression of the mechanosensor 5-HT_1B. In this study, we investigated the molecular mechanisms underlying OSS-induced 5-HT_1B upregulation in vivo and in vitro. Disturbed flow was induced in mice by partial carotid ligation. In vitro experiments were conducted in human aortic endothelial cells (HAECs) subjected to oscillatory shear stress using an ibidi flow system. We showed that oscillatory shear stress significantly upregulated the expression of 5-HT_1B in HAECs via activation of YAP, while knockout of YAP significantly reduced this upregulation. We demonstrated that YAP directly regulated the expression of HTR1B via binding to its promoter region. Inhibition of 5-HT_1B using its antagonist SB-216641 impeded YAP nuclear localization and endothelial activation in HAECs. We verified that a 5-HT_1B-YAP loop was also activated in atherosclerotic arteries of ApoE-/- mice. Endothelium-specific overexpression of YAP exacerbated atherosclerosis. Moreover, endothelium-specific knockout of 5-HT_1B or YAP inhibited disturbed flow-induced endothelial inflammation and plaque formation in ApoE-/- mice. Taken together, the 5-HT_1B-YAP positive feedback loop amplifies the pro-atherogenic effect of disturbed flow. We suggest that targeting 5-HT_1B-YAP loop holds promise as a novel therapeutic strategy for atherosclerotic diseases.