Functions of serotonin in hypoxic pulmonary vascular remodeling
Functions of serotonin in hypoxic pulmonary vascular remodeling
复制标题
DOI：
10.1385/cbb:47:1:33
复制
发表时间：
2007-01-01
影响因子：
2.6
通讯作者：
Maroteaux, Luc
中科院分区：
文献类型：
--
作者：
Esteve, Juan M.;Launay, Jean-Marie;Maroteaux, Luc
在肺血管系统中，平滑肌细胞的可逆收缩存在于对氧水平的急性降低（缺氧）的响应中。慢性缺氧会导致进行性和不可逆的结构重塑，导致肺动脉高压。几项研究表明，血清素在调节急性和慢性缺氧反应中的作用。本文就5-羟色胺及其受体和转运体在肺缺氧反应中的作用作一综述。低血糖状态改变血浆5-羟色胺水平、5-羟色胺转运体活性以及5-HT 1B和5-HT 2B受体的表达。这些似乎是肺血管细胞增殖所必需的，这取决于活性氧和一氧化氮之间的比例。一个杂合突变被确定在5-HT 2B受体基因的患者谁开发的肺动脉高压芬氟拉明治疗后。这种C-末端截短的5-HT 2B突变体受体呈现出比野生型受体更低的一氧化氮偶联和更高的细胞增殖能力。在低氧张力下，细胞通过稳定转录因子缺氧诱导因子（HIF）-1来增加特定基因的转录。血管紧张素II或凝血酶等因子也可以控制HIF-1通路，促进肺血管重塑。5-HT 2 B受体通过磷脂酰肌醇-3激酶/Akt激活核因子-κ B，其参与HIF-1表达的调节。5-HT 2B受体对HIFI的控制解释了为什么在缺氧5-HT 2B受体突变小鼠中，肺血管重塑因子（如内皮素-1或转化生长因子-β）的表达（受HIF-1-α调节）没有改变。了解肺低氧反应的详细机制可能有助于了解肺动脉高压的发病机制。
In lung vasculature, reversible constriction of smooth muscle cells exists in response to acute decrease in oxygen levels (hypoxia). Progressive and irreversible structural remodeling that reduces blood vessel lumen takes place in response to chronic hypoxia and results in pulmonary hypertension. Several studies have shown a role of serotonin in regulating acute and chronic hypoxic responses. In this review the contribution of serotonin, its receptors and transporter in lung hypoxic responses is discussed. Hypoxic conditions modify plasma levels of serotonin, serotonin transporter activity, and expression of 5-HT1B and 5-HT2B receptors. These appear to be required for pulmonary vascular cell proliferation, which depends on the ratio between reactive oxygen species and nitric oxide. A heterozygous mutation was identified in the 5-HT2B receptor gene of a patient who developed pulmonary hypertension after fenfluramines anorexigen treatment. This C-terminus truncated 5-HT2B mutant receptor presents lower nitric oxide coupling, and higher cell proliferation capacity than the wild-type receptor. Under low oxygen tension, cells increase the transcription of specific genes via stabilization of the transcription factor hypoxia-inducible factor (HIF)-1. Factors such as angiotensin II or thrombin that can also control HIF-1 pathway contribute to pulmonary vascular remodeling. The 5-HT2B receptor via phosphatidylinositol-3 kinase/Akt activates nuclear factor-kappa B, which is involved in the regulation of HIF-1 expression. A control of HIFI by 5-HT2B receptors explains why expression of pulmonary vascular remodeling factors, such as endothelin-1 or transforming growth factor-beta, which is HIF-1-alpha regulated, is not modified in hypoxic 5-HT2B receptor mutant mice. Understanding the detailed mechanisms involved in lung hypoxic responses may provide general insight into pulmonary hypertension pathogenesis.