Serotonin is a neurotransmitter in the central nervous system. In the periphery, serotonin functions as a ubiquitous hormone involved in vasoconstriction and platelet function. Serotonin is synthesized independently in peripheral tissues and neurons by two different rate-limiting tryptophan hydroxylase (TPH) isoenzymes. Here, we show that mice selectively deficient in peripheral TPH and serotonin exhibit impaired hemostasis, resulting in a reduced risk of thrombosis and thromboembolism, although the ultrastructure of the platelets is not affected. While the aggregation of serotonin-deficient platelets in vitro is apparently normal, their adhesion in vivo is reduced due to a blunted secretion of adhesive alpha-granular proteins. In elucidating the mechanism further, we demonstrate that serotonin is transamidated to small GTPases by transglutaminases during activation and aggregation of platelets, rendering these GTPases constitutively active. Our data provides evidence for a receptor-independent signaling mechanism, termed herein as "serotonylation," which leads to alpha-granule exocytosis from platelets.

The highly effective anorexigen (ϩ)-fenfluramine (Redux) was widely prescribed for the treatment of obesity until it was associated with primary pulmonary hypertension (Abenhaim et al., 1996) and aortic valvular disease (Connolly et al., 1997). We have reported previously that the hepatic deethylated metabolite of (ϩ)-fenfluramine, (ϩ)-norfenfluramine, is vasoactive. (ϩ)-Norfenfluramine causes contraction in isolated rat aorta, renal artery, and mesenteric resistance artery and increases blood pressure through activation of 5-hydroxytryptamine (5-HT) 2A receptor (Ni et al., 2004a).Recently, we found that 5-HT and a functional 5-HTT are present in rat peripheral arteries (Ni et al., 2004b). 5-HT is a vasoconstrictor and causes contraction in many arteries and veins, especially conduit vessels via 5-HT 2A receptors (Martin, 1994). (ϩ)-Fenfluramine and (ϩ)-norfenfluramine are 5-HTT substrates and potent 5-HT releasers (Garattini, 1995;Rothman and Baumann, 2002). Because the anorexic effect of (ϩ)-fenfluramine was considered to be due at least in part to 5-HT release (Fishman, 1999), we hypothesized that (ϩ)-norfenfluramine-induced vasoconstriction is dependent on release of endogenous 5-HT via 5-HTT with consequent 5-HT-induced activation of 5-HT 2A receptor-mediating contraction.We studied our hypothesis by using two different strains of mice. Aorta from tryptophan hydroxylase (TPH) 1-deficient

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