Pulmonary vascular remodeling is associated with pulmonary hypertension and is characterized by media thickening, disordered proliferation and often in situ thrombosis. However, the signaling pathways linking these processes are not well understood. The p21-activated kinase-1 (PAK-1) was shown to control growth, migration and prothrombotic activity, and the transcription factor HIF-1 was associated with pulmonary vascular remodeling. Here we studied the hypothesis that PAK-1 and HIF-1a are linked in pulmonary vascular remodeling. PAK-1 was highly expressed in the media of remodeled pulmonary vessels from patients with pulmonary vasculopathy and was upregulated together with Rac1 and HIF-1a in lung tissue from lambs with an aorto-pulmonary shunt. PAK-1 was activated by thrombin involving calcium and Rac1 resulting in enhanced generation of reactive oxygen species (ROS). Active PAK-1 mediated HIF-1 activation and enhanced HIF-1a expression involving ROS and NFkB. Subsequently, PAK-1 enhanced expression of the HIF-1 target gene plasminogen activator inhibitor-1 and promoted PASMC proliferation. Importantly, HIF-1 also promoted transcriptional upregulation of Rac1 and PAK-1. These findings present evidence that PAK-1 and its activator Rac1 are novel HIF-1 targets which constitute a positive feed back loop for induction of HIF-1a by thrombin and ROS. This mechanism may play an essential role in promoting pulmonary vascular remodeling.