A Serotonergic System in Veins: Serotonin Transporter-Independent Uptake

A. Elizabeth Linder; Wei Ni; Theodora Szasz; Robert Burnett; Jessica Diaz; Timothy J. Geddes; Donald M. Kuhn; Stephanie W. Watts

doi:10.1124/jpet.107.135699

Abstract

We hypothesized that the 5-hydroxytryptamine (5-HT; serotonin) system is present and functional in veins. In vena cava (VC), the presence of the 5-HT synthesis rate-limiting enzyme tryptophan hydroxylase-1 mRNA and accumulation of the 5-HT synthesis intermediate 5-hydroxytryptophan after incubation with tryptophan supported the ability of veins to synthesize 5-HT. The presence of 5-HT and its metabolite 5-hydroxyindole acetic acid was measured by high-performance liquid chromatography in VC and jugular vein (JV), and it was compared with similarly sized arteries aorta (RA) and carotid (CA), respectively. In rats treated with the monoamine oxidase-A (MAO-A) inhibitor pargyline to prevent 5-HT metabolism, basal 5-HT levels were higher in veins than in arteries. 5-HT uptake was observed after exposure to exogenous 5-HT in all vessels. The presence of MAO-A and the 5-HT transporter (SERT) in VC was observed by immunohistochemistry and Western analysis. However, 5-HT uptake was not inhibited by the SERT inhibitors fluoxetine and/or fluvoxamine in VC and JV, as opposed to the inhibition in RA and CA. Moreover, studies performed in VC from mutant rats lacking SERT showed no differences in 5-HT uptake compared with VC from wild type. These data suggest the SERT is not functional under physiological conditions in veins. The differences in 5-HT handling between veins and arteries may represent alternative avenues for targeting the 5-HT system in the peripheral circulation for controlling vascular tone.

Footnotes

This work was supported by National Institutes of Health Grant HL81115 (to S.W.W.) and American Heart Association Postdoctoral Fellowship 0725729Z (to A.E.L.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.107.135699.
ABBREVIATIONS: 5-HT, 5-hydroxytryptamine (serotonin); 5-HTP, 5-hydroxytryptophan; TPH, tryptophan hydroxylase; SERT, serotonin transporter; MAO, monoamine oxidase; 5-HIAA, 5-hydroxyindole acetic acid; KO, knockout; WT, wild type; B2m, β-2-microglobulin; PCR, polymerase chain reaction; HPLC, high-performance liquid chromatography; PBS, phosphate-buffered saline; NET, norepinephrine transporter; VC, vena cava; JV, jugular vein; RA, rat aorta; CA, carotid artery; BH₄, tetrahydrobiopterin.
- Received December 20, 2007.
- Accepted February 29, 2008.