Modification of 5-hydroxytryptamine (5-HT, serotonin) concentration or receptor stimulation has resulted in treatments for depression, feeding disorders and obesity. 5-HT is also a vascular smooth muscle cell mitogen and vasoconstrictor but a significant amount of work has produced equivocal results in terms of 5-HT modifying arterial tone in vivo in the control of systemic blood pressure. Importantly, the relevance of 5-HT to peripheral arterial function has been questioned because mechanisms for arterial handing and metabolism of 5-HT are unknown. Our overall hypothesis is that the serotonin transporter (SERT) is present in peripheral arteries and has physiological consequence in arterial function. We will use an integrated set of techniques - isolated tissue baths and myographs, immunohistochemistry, Westerns, cell culture, transporter activity assays, and telemetry -- in rats and mice to address two specific Aims:
Specific Aim #1 : To test the hypothesis that 5-HT is taken up and released from arterial smooth muscle by SERT. We hypothesize that 5-HT is actively taken up, released and potentially stored in peripheral arteries, functions dependent on SERT. Such findings build a case for a local serotonergic system in the artery, a system which should be regulated and modifiable if physiologically important. Thus, work in this aim is directed towards understanding functional regulation of SERT and testing for the presence of components that would form a local 5-HT system: synthesis, uptake, storage and release.
Specific Aim #2 : To test the hypothesis that SERT modifies arterial function with physiological consequence.
This aim builds on Aim 1 by studying two models in which SERT function has physiological relevance and thus enables illustration of the importance of 5-HT/SERT as it relates to modifying arterial contractility and blood pressure. The first model is the artery in which subthreshold concentrations of 5-HT potentiate arterial contraction to norepinephrine and endothelin, the second a model of hypertension. Collectively, these studies are important because they highlight the role of 5-HT in the peripheral cardiovascular system, and reveal a new functional role for SERT. Moreover, because SERT is a target for the commonly prescribed serotonin reuptake inhibitors such as ProzacZ, these studies provide potential insight into cardiovascular complications experienced by those taking SERT inhibitors. ? ? ?
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| Linder, Aurea Elizabeth; Davis, Robert Patrick; Burnett, Robert et al. (2011) Comparison of the function of the serotonin transporter in the vasculature of male and female rats. Clin Exp Pharmacol Physiol 38:314-22 |
| Watts, Stephanie W; Shaw, Samantha; Burnett, Robert et al. (2011) Indoleamine 2,3-diooxygenase in periaortic fat: mechanisms of inhibition of contraction. Am J Physiol Heart Circ Physiol 301:H1236-47 |
| Watts, Stephanie W; Davis, Robert Patrick (2011) 5-hydroxtryptamine receptors in systemic hypertension: an arterial focus. Cardiovasc Ther 29:54-67 |
| Watts, Stephanie W; Priestley, Jessica R C; Thompson, Janice M (2009) Serotonylation of vascular proteins important to contraction. PLoS One 4:e5682 |
| Linder, A Elizabeth; Ni, Wei; Szasz, Theodora et al. (2008) A serotonergic system in veins: serotonin transporter-independent uptake. J Pharmacol Exp Ther 325:714-22 |
| Ni, Wei; Zhou, Huawei; Diaz, Jessica et al. (2008) Lack of the serotonin transporter does not prevent mineralocorticoid hypertension in rat and mouse. Eur J Pharmacol 589:225-7 |
| Linder, A Elizabeth; Diaz, Jessica; Ni, Wei et al. (2008) Vascular reactivity, 5-HT uptake, and blood pressure in the serotonin transporter knockout rat. Am J Physiol Heart Circ Physiol 294:H1745-52 |
| Ni, W; Geddes, T J; Priestley, J R C et al. (2008) The existence of a local 5-hydroxytryptaminergic system in peripheral arteries. Br J Pharmacol 154:663-74 |
| Diaz, Jessica; Ni, Wei; Thompson, Janice et al. (2008) 5-Hydroxytryptamine lowers blood pressure in normotensive and hypertensive rats. J Pharmacol Exp Ther 325:1031-8 |
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