Calcification, fibrosis, and chronic inflammation are the predominant features 
of calcific aortic valve disease, a life-threatening condition. Drugs that 
induce serotonin (5-hydroxytryptamine [5-HT]) are known to damage valves, and 
activated platelets, which carry peripheral serotonin, are known to promote 
calcific aortic valve stenosis. However, the role of 5-HT in valve leaflet 
pathology is not known. We tested whether serotonin mediates 
inflammation-induced matrix mineralization in valve cells. Real-time reverse 
transcription-polymerase chain reaction analysis showed that murine aortic valve 
interstitial cells (VICs) expressed both serotonin receptor types 2A and 2B 
(Htr2a and Htr2b). Although Htr2a expression was greater at baseline, Htr2b 
expression was induced several-fold more than Htr2a in response to the 
pro-calcific tumor necrosis factor-α (TNF-α) treatment. 5-HT also augmented 
TNF-α-induced osteoblastic differentiation and matrix mineralization of VIC, but 
5-HT alone had no effects. Inhibition of serotonin receptor type 2B, using 
specific inhibitors or lentiviral knockdown in VIC, attenuated 5-HT effects on 
TNF-α-induced osteoblastic differentiation and mineralization. 5-HT treatment 
also augmented TNF-α-induced matrix metalloproteinase-3 expression, which was 
also attenuated by Htr2b knockdown. Htr2b expression in aortic roots and serum 
levels of peripheral 5-HT were also greater in the hyperlipidemic Apoe-/- mice 
than in control normolipemic mice. These findings suggest a new role for 
serotonin signaling in inflammation-induced calcific valvulopathy.