Vascular remodelling in pulmonary hypertension (PH) results from persistent vasoconstriction, smooth muscle cell growth and extracellular matrix (ECM) degradation, f.e. by matrix metalloproteinases (MMPs. Urotensin-II (hU-II) is a potent vasoconstrictor and has been associated with PH. We investigated whether hU-II can affect expression and activity of MMP2 and MMP9 in human pulmonary artery smooth muscle cells(PASMC). hU-II enhanced activity and expression of MMP2 in a time-dependent manner. In contrast, MMP9 activity was not detected. Consistently, strong expression of MMP2, but not MMP9, was observed in the media and intima of small pulmonary arteries with signs of vascular disease derived from patients with PH. Furthermore, stimulation of MMP2 expression and activity by hU-II was diminished by inhibition of NADPH oxidases, p38 MAP kinase and protein kinase B. Thus, our findings indicate that hU-II increases MMP2 expression and activity in PASMC bv stimulating ROS generation by NADPH oxidases and subsequent activation of p38 MAP kinase and protein kinase B. Since MMP2 protein was specifically present in small pulmonary arteries with signs of pulmonary vascular disease, this mechanism may play an important role in promoting vascular remodelling in PH.