Endothelial Serotonin Receptor 1B Acts as a Mechanosensor to Drive Atherosclerosis

BACKGROUND: Atherosclerosis is characterized by the accumulation of fatty and fibrotic plaques, which preferentially develop at curvatures and branches along the arterial trees that are exposed to disturbed flow. However, the mechanisms by which endothelial cells sense disturbed flow are still unclear. METHODS: The partial carotid ligation mouse model was used to investigate disturbed flow-induced atherogenesis. In vitro experiments were performed using the ibidi system to generate oscillatory shear stress and laminar shear stress. ApoE −/− mice with endothelium-specific knockout or overexpression of 5-HT 1B (serotonin receptor 1B) were used to investigate the role of endothelial 5-HT 1B in atherosclerosis. RNA sequencing analysis, immunofluorescence analysis, and molecular biological techniques were used to explore the role of 5-HT 1B in mechanotransduction and endothelial activation. RESULTS: The data showed that human endothelial cells express a high level of 5-HT 1B , which is a serotonin receptor subtype. Endothelial 5-HT 1B is upregulated in atherosclerotic areas of both humans and rodents and is increased by disturbed flow both in vivo and in vitro. Endothelium-specific overexpression of 5-HT 1B exacerbates, whereas knockout or knockdown of 5-HT 1B in endothelium inhibits disturbed flow-induced endothelial inflammation and atherogenesis in both male and female ApoE −/− mice. We reveal a previously unknown role of 5-HT 1B as a mechanosensor in endothelial cells in response to mechanical stimuli. Upon activation by oscillatory shear stress, 5-HT 1B recruits β-arrestin, orchestrates RhoA, and then activates mechanosensitive YAP (yes-associated protein), thereby enhancing endothelial inflammation and monocyte infiltration. Pharmacological blockade of 5-HT 1B suppresses endothelial activation and atherogenesis via inhibition of YAP. CONCLUSIONS: Taken together, these results uncover that endothelial 5-HT 1B acts as a mechanosensor for disturbed flow and contributes to atherogenesis. Inhibition of 5-HT 1B could be a promising therapeutic strategy for atherosclerosis.