Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene

Abstract

IntroductionExposure to chronic hypoxia leads to the development of pulmonary hypertension (PH) owing to persistent vasoconstriction and structural remodeling of pulmonary vessels. Proliferation of vascular smooth muscle cells (SMCs) is an important component of pulmonary vessel remodeling that results in increased thickness of the medial muscular coat in normally muscular arteries and in extension of muscle into smaller and more peripheral arteries (1). The mechanism by which hypoxia induces pulmonary SMCs' proliferation, however, is not well understood. One current hypothesis is that hypoxia may directly affect the expression of specific genes involved in pulmonary vascular SMC growth (2).The serotonin (5-hydroxytryptamine; 5-HT) transporter (5-HTT) in pulmonary vascular SMCs has many attributes suggesting that it may be a key determinant of pulmonary vessel remodeling. In addition to contributing to the uptake and subsequent inactivation of 5-HT passing through the lung, 5-HTT mediates the proliferation of pulmonary vascular SMCs through its ability to internalize indoleamine (3, 4). The requirement of 5-HTT as a mediator of 5-HT mitogenic activity appears specific for pulmonary vascular SMCs, since it has not been reported in other cell types (5). Moreover, exposure of pulmonary vascular SMCs to hypoxia increases 5-HTT expression and activity (3, 6), an effect associated with potentiation of the mitogenic action of 5-HT (6). Increased 5-HTT gene expression also occurs in remodeled pulmonary vessels of rats during PH development associated with chronic exposure to hypoxia (6). Because 5-HTT is a target for drugs that recently have been shown to increase the risk of PH development in humans (7), it may be of clinical relevance; therefore elucidation of its role in pulmonary vascular SMC proliferation is of interest. However, direct evidence for a role of 5-HTT in vessel remodeling during PH is lacking.The purpose of this study was to investigate whether 5-HTT deficiency affects the development of pulmonary vascular remodeling and PH during chronic hypoxia. We used mice with targeted disruption of the 5-HTT gene (5-HTT -/-) (8) and investigated their hemo- Hypoxia is a well-recognized stimulus for pulmonary blood vessel remodeling and pulmonary hypertension development. One mechanism that may account for these effects is the direct action of hypoxia on the expression of specific genes involved in vascular smooth muscle cell (SMC) proliferation. Previous studies demonstrated that the serotonin (5-hydroxytryptamine; 5-HT) transporter (5-HTT) mediates the mitogenic activity of 5-HT in pulmonary vascular SMCs and is overexpressed during hypoxia. Thus, 5-HT-related mitogenic activity is increased during hypoxia. Here, we report that mice deficient for 5-HTT (5-HTT -/-) developed less hypoxic pulmonary hypertension and vascular remodeling than paired 5-HTT +/+ controls. When maintained under normoxia, 5-HTT -/--mutant mice had normal hemodynamic parameters, low blood 5-HT levels, deficient platelet 5-HT uptake, and u...

Pathology of Pulmonary Hypertension

“…Vascular smooth muscle cells in IPAH lungs express higher levels of 5-HTT [53] or 5-HT 2B R [52] by immunohistochemistry, and undergo enhanced cell proliferation when treated in vitro with serotonin compared with normal smooth muscle cells [53]. These findings are supported by the report that mice deficient in 5HTT or 5-HT-2B are protected against PH caused by hypoxia alone [52] or hypoxia combined with the anorexigen dexfenfluramine [54], respectively. Of interest is the observation that increased serotonin levels affect signaling pathways downstream of mutated BMPR2, as serotonin infusion enhances normoxic and hypoxic pulmonary pressures and vascular remodeling in BMPR2 heterozygous mice as compared with wild type mice [50].…”

Hypoxia and chronic lung disease

“…Serotonin (5-HT) could affect pulmonary vascular remodeling, as it promotes vasoconstriction and vascular smooth muscle cell growth [51]. Hypoxia modifies plasma levels of serotonin, serotonin transporter activity, and expression of 5-HT 1B and 5-HR 2B receptors [52]. However, rather than 5-HT transporters, serotonin receptors might instead mediate hypoxic PH as demonstrated by the protection against hypoxic PH documented in mice lacking 5-HT 2B receptors [53].…”

Activation of GATA-4 by Serotonin in Pulmonary Artery Smooth Muscle Cells

“…Proliferation of smooth muscle cells is an important component of pulmonary vascular remodeling that results in increased medial muscular wall thickness. Among a number of mediators of pulmonary hypertension, serotonin (5-hydroxytryptamine (5-HT) 1 ) appears to play an important role in the remodeling of the pulmonary circulation (1)(2)(3).…”