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

Abstract

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 (ras homolog family member A), 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.

Keywords: atherosclerosis; endothelial cells; endothelium, vascular; inflammation; mechanotransduction, cellular.