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Djordjevic, Talija (2006): Signaling through NADPH oxidases: role in vascular remodeling processes. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

Vascular remodeling processes are characterized by increased proliferation of vascular cells and a prothrombotic state. Coagulation factors and vasoactive peptides have been suggested to contribute to these processes. Reactive oxygen species (ROS) have been implicated to act as vascular signaling molecules, and NADPH oxidases have been identified as a major source of vascular ROS production. The aims of the present study were therefore to identify signaling pathways linking factors promoting remodeling processes such as thrombin and the vasoactive peptide urotensin-II to ROS production derived from NADPH oxidases as well as subsequent proliferation and procoagulant activity. Thrombin induced a biphasic increase in ROS levels. A rapid activation of NADPH oxidases was followed by a second delayed response. This increase was paralleled by ROSdependent induction of p22phox involving p38MAPK and PI3K/Akt in endothelial cells, and by enhanced Rac-1 levels in pulmonary artery smooth muscle cells, and followed by enhanced proliferation. Activation of Rac-1-dependent ROS production by thrombin resulted in elevated levels of the prothrombotic factors tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) in PASMC. Rac-1-dependent induction of TF was mediated by the transcription factor NF?B and resulted in enhanced procoagulant activity. Since active TF results in thrombin generation, this pathway could play an important role in promoting a feedback loop leading to a thrombogenic cycle. Rac-1-dependent induction of PAI-1 was mediated by elevated Ca2+, the Rac-1 downstream target PAK and the transcription factor HIF-1. Since PAI-1 inhibition diminished proliferation of PASMC, these findings identify PAI-1 as an important mediator of thrombin-stimulated NADPH oxidase-dependent proliferation. Finally, the vasoactive peptide U-II was identified as a novel activator of NADPH oxidases and ROS-dependent activation of MAP kinases and Akt which subsequently induced PAI-1 expression and proliferation. Taken together, these findings support a model where enhanced levels of thrombotic and vasoactive factors, as found in an early stage of vascular remodeling, activate and induce NADPH oxidases and ROS generation. ROS-dependent signaling cascades link and amplify these signals and promote proliferative and thrombotic events which can lead to progression of vascular remodeling.