Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension

Abstract

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...

Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin α v β 3 /FAK/AKT Pathway Suppression

“…Indeed, osteoprotegerin secretion could be elevated in PASMCs by reduced bone morphogenic proteins receptor 2 (BMR-R2) expression and increased expression of 11 which play critical roles in PAH pathogenesis. 25,26 The theorized role of osteoprotegerin in PAH was based on clinical data and experimental evidence without specific interventions, 11,13 where direct proof from genetic models is lacking. Our results address this gap, as osteoprotegerin disruption inhibited PASMC proliferation and mitigated disease severity in HySu-induced PAH animal model.…”

“…25,26 The theorized role of osteoprotegerin in PAH was based on clinical data and experimental evidence without specific interventions, 11,13 where direct proof from genetic models is lacking. Our results address this gap, as osteoprotegerin disruption inhibited PASMC proliferation and mitigated disease severity in HySu-induced PAH animal model.…”

Aspirin Attenuates Pulmonary Arterial Hypertension in Rats by Reducing Plasma 5-Hydroxytryptamine Levels

“…A high level of plasma 5-HT promotes PASMC hyperplasia. In addition, PASMCs from PAH patients grow faster than those PASMCs from control subjects, which is partly due to increased expression of the 5-HT transporter [15]. Overexpressing the 5-HT transporter gene in smooth muscle causes pulmonary hypertension [16].…”

Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future

“…However, unlike the 5-HT 1B receptor, there is currently no evidence that the 5-HT 2B receptor mediates vasoconstriction of human pulmonary arteries. There is continuing debate concerning the role of 5-HT 2B receptor-mediated proliferation of human pulmonary arterial smooth muscle cells or pulmonary arterial fibroblasts (Dumitrascu et al, 2011;Eddahibi et al, 2001;Marcos et al, 2003). Interestingly, there is a case report of a patient with a loss-of-function mutation in 5-HT 2B with fenfluramine-associated primary pulmonary hypertension (Blanpain et al, 2003).…”