Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension
Saadia Eddahibi, … , Michel Hamon, Serge Adnot
Saadia Eddahibi, … , Michel Hamon, Serge Adnot
Published October 15, 2001
Citation Information: J Clin Invest. 2001;108(8):1141-1150. https://doi.org/10.1172/JCI12805.
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Article

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

Abstract

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 susceptibility to PPH.

Authors

Saadia Eddahibi, Marc Humbert, Elie Fadel, Bernadette Raffestin, Michèle Darmon, Frédérique Capron, Gerald Simonneau, Philippe Dartevelle, Michel Hamon, Serge Adnot

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Figure 3

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5-HTT–like immunoreactivity in lung sections from control subjects and p...
5-HTT–like immunoreactivity in lung sections from control subjects and patients with PPH. (a) A lung section from a control subject with a weak to moderate 5-HTT–like immunoreactivity in pulmonary arterial endothelial cells and strong immunoreactivity in SMCs. (b–d) Lung sections from patients with PPH: 5-HTT–like immunoreactivity is much stronger, especially in the medial layer of pulmonary arteries with marked muscular hypertrophy (b). No 5-HTT immunostaining is detected in intimal fibrosis (c). In lesions with onion-bulb arrangement, 5-HTT–like immunoreactivity is prominent at sites of intense PA-SMC proliferation (d). (e) No immunoreactivity is detected in a section incubated with secondary Ab, but no primary Ab. Scale bar: 100 μm in a, b, c, and e; 200 μm in d.