Genetic ablation of serotonin receptor 2B improves aortic valve hemodynamics in a high-cholesterol diet mouse model

Calcific aortic valve disease (CAVD) is a deadly disease that is rising in prevalence due to population aging. While the disease is complex and poorly understood, one well-documented driver of valvulopathy is serotonin agonism. Both serotonin overexpression, as seen with carcinoid tumors and drug-related agonism, such as with Fenfluramine use, are linked with various diseases of the valves. Thus, the objective of this study was to determine if genetic ablation or pharmacological antagonism of the 5-HT2Bserotonin receptor (gene:Htr2b) could improve the hemodynamic and histological progression of calcific aortic valve disease.Htr2bmutant mice were crossed withNotch1+/-mice, an established small animal model of CAVD, to determine if genetic ablation affects CAVD progression. To assess the effect of pharmacological inhibition on CAVD progression,Notch1+/-mice were treated with the 5-HT2Breceptor antagonist SB204741. Mice were analyzed using echocardiography, histology, immunofluorescence, and real-time quantitative polymerase chain reaction.Htr2bmutant mice showed lower aortic valve peak velocity and mean pressure gradient – classical hemodynamic indicators of aortic valve stenosis – without concurrent left ventricle change. 5-HT2Breceptor antagonism, however, did not affect hemodynamic progression. Leaflet thickness, collagen density, and CAVD-associated transcriptional markers were not significantly different in any group. This study reveals that genetic ablation ofHtr2battenuates hemodynamic development of CAVD in theNotch1+/-mice, but pharmacological antagonism may require high doses or long-term treatment to slow progression.