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

Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of primary pulmonary hypertension (PPH). Here we foun d that PA-SMCs from patients with PPH grow faster than PA-SMCs from control s when stimulated by serotonin or serum and that these effects are due to i ncreased expression of the serotonin transporter (5-HTT), which mediates in ternalization of indoleamine. In the presence of 5-HTT inhibitors, the grow th stimulatory effects of serum and serotonin were markedly reduced and the difference between growth of PA-SMCs from patients and controls was no lon ger observed. As compared with controls, the expression of 5-HTT was increa sed in cultured PA-SMCs as well as in platelets and lungs from patients wit h PPH where it predominated in the media of thickened pulmonary arteries an d in onion-bulb lesions. The L-allelic variant of the 5HTT gene promoter, w hich is associated with 5-HTT overexpression and increased PA-SMC growth, w as present in homozygous form in 65% of patients but in only 27% of control s. 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 lity to PPH.