(137e) Serotonin Control of the Activated and Osteoblastic Phenotypes of Valvular Interstitial Cells

Degenerative valvular heart diseases can be regarded as resultant of the mechanochemical environment where cells reside. This study investigates how serotonin, a small molecule involved in a number of biological processes including valvular degeneration, regulates valvular interstitial cell acquisition of activated (aVIC) or osteoblastic (obVIC) phenotypes. Valvular interstitial cells (VIC) are fibroblast-like cells, which have the ability to transform into an activated phenotype (aVIC) marked by increased alpha-smooth muscle actin or alternatively, into osteoblast-like cells (obVIC) marked by bone proteins. Each of these phenotypes is characteristic of specific degenerative valvular diseases. Primary valvular interstitial cell cultures were established on soft substrates in osteogenic media and markers of each specific phenotype were monitored over 8 days. We observed that osteogenic culture conditions drive the acquisition of osteoblastic phenotypes strongly in aortic VIC when compared to mitral VIC. The transformation to activated phenotype is also observed under osteogenic conditions. This finding is in agreement with naturally-occurring valvular degeneration modes (calcific versus myxomatous). In both mitral and aortic VICs, phenotype transformation to obVIC was observed as an early change followed by increased number of aVICs. In a different set of experiments, inhibitors of serotonin signaling (serotonin type 2 receptors and tryptophan hydroxylase 1 inhibitors) were used to assess the effects of serotonin signals on the distinct phenotypes. We observed that inhibition of serotonin signals reversed phenotype transformation, which was assessed using markers of expression of activated and osteogenic markers, calcium and collagen deposits. These results lead to the conclusion that aortic interstitial cells have higher potential for calcification than mitral interstitial cells and that such potential is regulated at least partly by serotonin signals. These findings provided a better understanding of signaling pathway regulating valvular cell phenotype transformation and can contribute to the development of effective therapeutic strategies of degenerative valvular diseases.