Elevated cyclic stretch and serotonin result in altered aortic valve remodeling via a mechanosensitive 5-HT(2A) receptor-dependent pathway.

INTRODUCTION

Serotonin/5-hydroxytryptamine (5-HT) has been implicated in valve disease and in the modulation of valve mechanical properties. Several 5-HT receptor subtypes are also known to be mechanosensitive in other cell types, but this has not been studied in the context of the valve. In this study, we sought to understand the effects of elevated 5-HT levels and stretch overload on aortic valve remodeling and the dominant 5-HT receptor subtype that regulates these processes.

METHODS AND RESULTS

Collagen biosynthesis and tissue mechanical properties of porcine aortic valve cusps were evaluated after 10% (physiologic) and 15% (pathologic) dynamic stretch. These studies were performed in normal medium or medium supplemented with 5-HT (1, 10, 100 μM) in the absence and presence of 5-HT(2A) or 5-HT(2B) receptor antagonists. Fresh valves served as controls. Valve collagen content was maximal at the 10-μM 5-HT concentration for both 10% and 15% stretch. The 5-HT(2A) receptor antagonist reduced collagen synthesis, cell proliferation, and hsp47 expression under elevated and normal stretch, whereas the 5-HT(2B) receptor antagonist was effective only at normal stretch. The pretransition stiffness of the valve cusps was also increased in response to 5-HT via a stretch-sensitive 5-HT(2A) mechanism, with the post-transition stiffness unaltered.

CONCLUSIONS

Combined elevated stretch and 5-HT resulted in increased valve collagen biosynthesis, cell proliferation, and tissue stiffness. These responses were inhibited by a 5-HT(2A) antagonist. This strongly suggests that the 5-HT(2A) receptor subtype is sensitive to elevated stretch.