Distinct signaling pathways activated by "extracellular" and "intracellular" serotonin in heart valve development and disease.

Cardiac valve diseases are often due to developmental anomalies that progressively lead to the abnormal distribution and organization of extracellular matrix proteins overtime. Whereas mechanisms underlying adult valvulopathies are unknown, previous work has shown a critical involvement of the monoamine serotonin in disease pathogenesis. In particular, the interaction of serotonin with its receptors can activate transforming growth factor-β1 (TGF-β1) signaling, which in turn promotes extracellular matrix gene expression. Elevated levels of circulating serotonin can lead to aberrant TGF-β1 signaling with significant effects on cardiac valve structure and function. Additional functions of serotonin have recently been reported in which internalization of serotonin, through the serotonin transporter SERT, can exert important cytoskeletal functions in lieu of simply being degraded. Recent findings demonstrate that intracellular serotonin regulates cardiac valve remodeling, and perturbation of this pathway can also lead to heart valve defects. Thus, both extracellular and intracellular mechanisms of serotonin action appear to be operative in heart valve development, functionality, and disease. This review summarizes some of the salient aspects of serotonin activity during cardiac valve development and disease pathogenesis with an understanding that further elaboration of intracellular and extracellular serotonin pathways may lead to beneficial treatments for heart valve disease.