Pulmonary arterial hypertension (PAH) can be characterised by vasoconstriction and remodelling of the pulmonary artery. Patients with familial PAH can demonstrate increased expression/activity of the 5HT transporter (5HTT) (1). Rho-kinase (ROCK) may play a role in vasoconstriction (2) and remodelling of the pulmonary arteries (3). In addition to this, there may be cross-talk between 5HT and the ROCK signalling pathways (4). Here we investigate the role of ROCK in chronic hypoxia-induced PAH in wild-type (WT) mice and mice that over-express the 5HTT (5HTT) (5). Female mice (C57BL/6 x CBA, WT and 5HTT+, 5-6 months) were maintained in hypoxic (10% 02) or normoxic conditions for 14 days. Mice were dosed daily with vehicle or the ROCK inhibitor Y27632 (30mg/kg) by oral gavage. Subsequently, under anaesthesia, systolic right ventricular pressure (sRVP) was obtained by direct, transdiaphragmatic, right ventricular cannulation. Right ventricular hypertrophy(RVH) was also assessed by determining the ratio of right ventricular free wall to left ventrical plus septum (RV/LV+S). RNA extracted from whole lung tissue was also analysed by real-time fluorogenic reverse transcription-PCR in order to determine the relative levels of ROCK 1 transcript abundance. Under normoxic conditions 5HTT+ mice had elevated sRVP compared to WT (WT: 18.7± 1.2mmHg (n=8), TG: 27.6±3.4mmHg, p<0.05). Exposure to chronic hypoxia was found to significantly increase sRVP in both WT and 5HTT+ mice (WT hypoxia: 30.5±1.8mmHg, n=5, p<0.01 versus normoxic. 5HTT+ hypoxic: 41.7±3.1 mmHg, n=5, p<0.01 versus normoxic). Treatment with Y27632 attenuated this response in WT (24.5±1.6 mmHg, n=8, p<0.05 versus hypoxia) and 5HTT+ mice (23.8±3.1, n=8, p<0.01 versus hypoxia). Chronic hypoxia also increased RVH in both WT and 5HTT+ mice(WT: 0.27±0.01, n=12 to 0.39±0.01, n=15, p<0.001. 5HTT+: 0.29±0.03 n=14 to 0.39±0.01 n=15, p<0.001). Dosing with Y27632 had no effect on RVH in WT mice (0.35±0.02 n=9) but significantly reduced RVH in 5HTT+ mice (0.33±0.01 n=9, p<0.001 versus hypoxic). Moreover, levels of ROCK 1 transcript were significantly elevated by chronic hypoxia in 5HTT+ mice (5.9±1.5, n=5 to 61±16.6, n=5, p<0.01) but not in WT mice (7.9±1.4, n=5 to 27.6±5.7, n=5). In summary, the beneficial effects of ROCK inhibition on sRVP are more pronounced in 5HTT+ mice. Furthermore, the ability of Y27632 to reduce right ventricular hypertrophy in 5HTT+ mice but not WT mice suggests cross-talk between 5HT and ROCK signalling systems. This is consistent with the marked elevation in the expression of ROCK 1 observed in the lungs of 5HTT+ mice in response to hypoxia.