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

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 specifi c genes involved in vascular smooth muscle cell (SMC) proliferation. Previo us studies demonstrated that the serotonin (5-hydroxytryptamine; 5-HT) tran sporter (5-HTT) mediates the mitogenic activity of 5-HT in pulmonary vascul ar SMCs and is overexpressed during hypoxia. Thus, 5-HT-related mitogenic a ctivity is increased during hypoxia. Here, we report that mice deficient fo r 5-HTT (5-HTT-/-) developed less hypoxic pulmonary hypertension and vascul ar remodeling than paired 5-HTT+/+ controls. When maintained under normoxia , 5-HTT-/--mutant mice had normal hemodynamic parameters, low blood 5-HT le vels, deficient platelet 5-HT uptake, and unchanged blood levels of 5-hydro xyindoleacetic acid, a metabolite of 5-HT After exposure to 10% O-2 for 2 o r 5 weeks, the number and medial wall thickness of muscular pulmonary vesse ls were reduced in hypoxic 5-HTT-/- mice as compared with wild-type paired controls. Concomitantly, right ventricular systolic pressure was lower and right ventricle hypertrophy less marked in the mutant mice. This occurred d espite potentiation of acute hypoxic pulmonary vasoconstriction in the 5-HT T(-/-)mice. These data further support a key role of 5-HTT in hypoxia-induc ed pulmonary vascular SMC proliferation and pulmonary hypertension.