IntroductionPulmonary hypertension (PH) is characterized by an increase in pulmonary vascular resistance that impedes ejection of blood by the right ventricle and leads to right ventricular failure. Primary PH (PPH) is the clinical term used to describe a rare and fatal condition for which no underlying cause can be found (1). Its pathogenesis remains largely unknown, although recent reports of familial PPH associated with BMPR2 gene mutations suggest a role for genetic predisposition (2, 3). Histologically, the remodeled pulmonary arteries show various degrees of medial hypertrophy and intimal thickening that, ultimately, lead to obliteration of the vessels. Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is the main component of these changes (4). Its origin, however, remains unknown.Investigations on serotonin, 5-hydroxytryptamine (5-HT), and its transporter (5-HTT) in patients with PPH are of special interest because an increased risk of PPH has been reported in patients who used appetite suppressants interfering with 5-HT (5). In previous studies, we found that 5-HT promoted the development of hypoxic PH by stimulating PA-SMC growth (6). As shown in bovine and rat PA-SMCs, the mitogenic and comitogenic effects of 5-HT require internalization of indoleamine by a high-affinity and selective transporter (7,8). Exposure of PA-SMCs to hypoxia results in a rapid increase in 5-HTT expression and activity, together with a marked enhancement in the growth-promoting effect of 5-HT (7). Increased 5-HTT gene expression also occurs in remodeled pulmonary arteries from animals developing PH related to chronic hypoxia exposure (7). Moreover, mice with targeted disruption of the 5-HTT gene develop less severe hypoxic PH than wild-type controls (9), which is direct evidence that 5-HTT plays a key role in pulmonary vessel remodeling. Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of primary pulmonary hypertension (PPH). Here we found that PA-SMCs from patients with PPH grow faster than PA-SMCs from controls when stimulated by serotonin or serum and that these effects are due to increased expression of the serotonin transporter (5-HTT), which mediates internalization of indoleamine. In the presence of 5-HTT inhibitors, the growth stimulatory effects of serum and serotonin were markedly reduced and the difference between growth of PA-SMCs from patients and controls was no longer observed. As compared with controls, the expression of 5-HTT was increased in cultured PA-SMCs as well as in platelets and lungs from patients with PPH where it predominated in the media of thickened pulmonary arteries and in onion-bulb lesions. The L-allelic variant of the 5HTT gene promoter, which is associated with 5-HTT overexpression and increased PA-SMC growth, was present in homozygous form in 65% of patients but in only 27% of controls. We conclude that 5-HTT activity plays a key role in the pathogenesis of PA-SMC proliferation in PPH and that a 5HTT polymorphism confers susceptibi...

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...

Our data indicate that the treatment of OSA in CAD patients is associated with a decrease in the occurrence of new cardiovascular events, and an increase in the time to such events.

To determine whether exposure to chronic hypoxia and subsequent development of pulmonary hypertension induces alterations of endothelium-dependent relaxation in rat pulmonary vascular bed, we studied isolated lung preparations from rats exposed to either room air (controls) or hypoxia (H) during 1

IntroductionPulmonary hypertension (PH) is characterized by an increase in pulmonary vascular resistance that impedes ejection of blood by the right ventricle and leads to right ventricular failure. Primary PH (PPH) is the clinical term used to describe a rare and fatal condition for which no underlying cause can be found (1). Its pathogenesis remains largely unknown, although recent reports of familial PPH associated with BMPR2 gene mutations suggest a role for genetic predisposition (2, 3). Histologically, the remodeled pulmonary arteries show various degrees of medial hypertrophy and intimal thickening that, ultimately, lead to obliteration of the vessels. Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is the main component of these changes (4). Its origin, however, remains unknown.Investigations on serotonin, 5-hydroxytryptamine (5-HT), and its transporter (5-HTT) in patients with PPH are of special interest because an increased risk of PPH has been reported in patients who used appetite suppressants interfering with 5-HT (5). In previous studies, we found that 5-HT promoted the development of hypoxic PH by stimulating PA-SMC growth (6). As shown in bovine and rat PA-SMCs, the mitogenic and comitogenic effects of 5-HT require internalization of indoleamine by a high-affinity and selective transporter (7,8). Exposure of PA-SMCs to hypoxia results in a rapid increase in 5-HTT expression and activity, together with a marked enhancement in the growth-promoting effect of 5-HT (7). Increased 5-HTT gene expression also occurs in remodeled pulmonary arteries from animals developing PH related to chronic hypoxia exposure (7). Moreover, mice with targeted disruption of the 5-HTT gene develop less severe hypoxic PH than wild-type controls (9), which is direct evidence that 5-HTT plays a key role in pulmonary vessel remodeling. Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of primary pulmonary hypertension (PPH). Here we found that PA-SMCs from patients with PPH grow faster than PA-SMCs from controls when stimulated by serotonin or serum and that these effects are due to increased expression of the serotonin transporter (5-HTT), which mediates internalization of indoleamine. In the presence of 5-HTT inhibitors, the growth stimulatory effects of serum and serotonin were markedly reduced and the difference between growth of PA-SMCs from patients and controls was no longer observed. As compared with controls, the expression of 5-HTT was increased in cultured PA-SMCs as well as in platelets and lungs from patients with PPH where it predominated in the media of thickened pulmonary arteries and in onion-bulb lesions. The L-allelic variant of the 5HTT gene promoter, which is associated with 5-HTT overexpression and increased PA-SMC growth, was present in homozygous form in 65% of patients but in only 27% of controls. We conclude that 5-HTT activity plays a key role in the pathogenesis of PA-SMC proliferation in PPH and that a 5HTT polymorphism confers susceptibi...