Serotonin (5-hydroxytrypatmine, 5-HT) regulates diverse processes in both the central nervous system (e.g. cognition, perception, mood, feeding behaviour) and the periphery (e.g. smooth muscle contractility, platelet aggregation). As such, dysregulation in the 5-HT system has been shown to contribute to several pathophysiological states, including depression, migraine headaches, and, more recently, some cardiovascular diseases.
During my thesis research with Bryan Roth, we demonstrated that 5-HT, the level s of which are elevated in carcinoid syndrome, causes heart valve fibrosis (i.e. cardiac valvulopathy) via activation of 5-HT2B receptors. An additional cardiovascular complication stemming from 5-HT levels is pulmonary hypertension (PH). Prof. Maroteaux has shown, using genetic and pharmacological approaches, that functional 5-HT2B receptors are required for the development of PH in the hypoxic mouse model of the disease. Also, Prof. Maroteaux's in vivo studies have shown that decreased 5-HT2B receptor function prevents hypoxia-induced increases in plasma 5-HT. Thus, 5-HT2B receptors appear to play an unappreciated role in 5-HT synthesis, release, and/or uptake in the cardiovascular system and likely elsewhere (e.g. the CNS).
Indeed, preliminary findings from Prof. Maroteaux's group reveal a role for 5-HT2B receptors in the plasma membrane targeting of the 5-HT transporter (SERT), suggesting that 5-HT2B receptors affect 5-HT levels by modulating SERT function. Thus, Prof. Maroteaux and I propose to characterize, through in vitro and tissue-specific in vivo studies, the mechanism of 5-HT2B receptors regulate SERT function and 5-HT levels in the cardiovascular system. These studies are likely to uncover previously unidentified mechanisms regulating 5-HT in the cardiovascular system; mechanisms that may be pertinent in the CNS. As such, our efforts could lead to novel strategies to treat cardiovascular diseases and, possibly, psychiatric disorders.
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