Specific serotonin receptor antagonist reduces murine calcific atherosclerosis

High levels of peripheral serotonin, produced in the gut, are associated with increased cardiovascular disease risk and bone loss. We previously found that vascular smooth muscle and valvular cells express serotonin receptors, predominantly type 2A (HTR-2A) at baseline and type 2B (HTR-2B) upon TNF-a stimulation. Serotonin treatment augmented TNF-a-induced matrix calcification, whereas the inhibitor of gut serotonin, LP533401, blunted the initiation, but not the progression, of cardiovascular calcification in Apoe^-/- mice. In this study, we tested which receptor subtypes mediated the effects of serotonin on cardiovascular calcification. Male and female Apoe^-/- mice with existing cardiovascular calcification were treated with vehicle, ketanserin (HTR-2A inhibitor), or LY272015 (HTR-2B inhibitor) for 8 weeks, and cardiovascular calcification, cardiac function, atherosclerosis, and lumbar vertebral bone density were assessed. Results showed cardiovascular calcification progressed in all groups, but in males, ketanserin treatment significantly inhibited the progression compared to the other groups. This effect was not observed in females. Echocardiographic analysis showed some changes in left ventricular wall thickness in the control mice but not in the ketanserin- or LY272015-treated mice, in both sexes. Cardiac functional indices were not significantly affected by the treatments. As for atherosclerotic lesions, ketanserin-treated females had fewer lesions than vehicle or LY272015-treated mice, but this was not observed in males. As for the lumbar vertebrae, LY272015-treated mice had significant bone loss in male, but not female, mice. These findings suggest that HTR-2 inhibitors have differential effects on cardiovascular calcification, cardiac structure, atherosclerosis, and vertebral bone loss in a sex and receptor subtype-dependent manner.