Role of NF-kappaB in flow-induced vascular remodeling.

Vascular remodeling associated with increased blood flow involves reactive oxygen species (ROS)-dependent activation of matrix metalloproteinases (MMPs). To investigate the potential role of NF-kappaB in this process, human umbilical vein endothelial cells were subjected to different flow conditions during a 24-h period. Normal (15 dynes/cm(2)) and high (30 dynes/cm(2)) shear stress induced IkappaBalpha degradation and NF-kappaB p65 phosphorylation, and activated MMP-2 and MMP-9. These effects were blunted in cells incubated with the NF-kappaB inhibitor pyrrolidine dithio-carbamate (PDTC). In mice, creation of a carotid artery-jugular vein arteriovenous fistula (AVF) increased carotid blood flow sixfold, triggering the increase in carotid diameter from 459 +/- 8 microm (before AVF) to 531 +/- 13 and 669 +/- 21 microm (7 and 21 days after AVF). ROS production and NF-kappaB activity were enhanced in fistulated carotids, but only the latter was blocked by PDTC, although PDTC blocked ROS production in vitro. In PDTC-treated mice, changes in carotid caliber and shear stress matched controls at 7 days, but carotids enlarged only marginally thereafter, reaching only 578 +/- 8 microm at 21 days (p < 0.01 vs. untreated). Similarly, both MMP-9 expression and activity were abrogated by PDTC at 3 weeks. Hence, induction of NF-kappaB by shear stress contributes to MMP induction and allows long-term flow-induced vascular enlargement.