Arterial 5-HT Transporter Function

描述（由申请人提供）：修改5-羟色胺（5-HT， 5-羟色胺）浓度或受体刺激已导致抑郁症，进食障碍和肥胖的治疗。5-羟色胺也是一种血管平滑肌细胞有丝分裂原和血管收缩剂，但大量的研究工作在5-羟色胺调节体内动脉张力以控制全身血压方面产生了模棱两可的结果。重要的是，5-HT与外周动脉功能的相关性一直受到质疑，因为5-HT的动脉处理和代谢机制尚不清楚。我们的总体假设是血清素转运体（SERT）存在于外周动脉中，并对动脉功能有生理影响。我们将在大鼠和小鼠中使用一整套技术-分离组织浴和肌图，免疫组织化学，western，细胞培养，转运蛋白活性测定和遥测，以解决两个特定目的：特定目的#1：验证SERT从动脉平滑肌中摄取和释放5-羟色胺的假设。我们假设5-HT被主动摄取、释放并可能储存在外周动脉中，其功能依赖于SERT。这些发现为动脉中的局部血清素能系统建立了一个案例，如果生理上重要的话，这个系统应该被调节和修改。因此，这方面的工作旨在了解SERT的功能调控，并测试构成局部5-羟色胺系统的成分：合成、摄取、储存和释放。具体目的#2：验证SERT改变动脉功能并产生生理后果的假设。该目标建立在目标1的基础上，通过研究SERT功能具有生理相关性的两个模型，从而能够说明5-HT/SERT与调节动脉收缩性和血压有关的重要性。第一个模型是动脉，阈下浓度的5-羟色胺增强动脉收缩产生去甲肾上腺素和内皮素，第二个模型是高血压。总的来说，这些研究很重要，因为它们突出了5-HT在外周心血管系统中的作用，并揭示了SERT的新功能作用。此外，由于SERT是常用的血清素再摄取抑制剂（如ProzacZ）的靶点，这些研究为服用SERT抑制剂的患者所经历的心血管并发症提供了潜在的见解。

DESCRIPTION (provided by applicant): 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.