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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:42.)
© 2007 American Heart Association, Inc.

Vascular Biology

Nox4 Is Required for Maintenance of the Differentiated Vascular Smooth Muscle Cell Phenotype

Roza E. Clempus; Dan Sorescu; Anna E. Dikalova; Lily Pounkova; Patricia Jo; George P. Sorescu; Bernard Lassègue; Kathy K. Griendling

From the Department of Medicine, Division of Cardiology, Emory University, Atlanta, Ga.

Correspondence to Kathy K. Griendling, Emory University, Division of Cardiology, 319 WMB, 1639 Pierce Dr, Atlanta, GA 30322. E-mail kgriend{at}emory.edu

Objective— The mechanisms responsible for maintaining the differentiated phenotype of adult vascular smooth muscle cells (VSMCs) are incompletely understood. Reactive oxygen species (ROS) have been implicated in VSMC differentiation, but the responsible sources are unknown. In this study, we investigated the role of Nox1 and Nox4-derived ROS in this process.

Methods and Results— Primary VSMCs were used to study the relationship between Nox homologues and differentiation markers such as smooth muscle -actin (SM -actin), smooth muscle myosin heavy chain (SM-MHC), heavy caldesmon, and calponin. We found that Nox4 and differentiation marker genes were downregulated from passage 1 to passage 6 to 12, whereas Nox1 was gradually upregulated. Nox4 co-localized with SM -actin–based stress fibers in differentiated VSMC, and moved into focal adhesions in de-differentiated cells. siRNA against nox4 reduced NADPH-driven superoxide production in serum-deprived VSMCs and downregulated SM- actin, SM-MHC, and calponin, as well as SM- actin stress fibers. Nox1 depletion did not decrease these parameters.

Conclusion— Nox4-derived ROS are critical to the maintenance of the differentiated phenotype of VSMCs. These findings highlight the importance of identifying the specific source of ROS involved in particular cellular functions when designing therapeutic interventions.

The mechanisms responsible for maintaining the differentiated phenotype of adult vascular smooth muscle cells (VSMCs) are incompletely understood. Reactive oxygen species (ROS) have been implicated in VSMC differentiation, but the responsible sources are unknown. In this study, we investigated the role of Nox1 and Nox4-derived ROS in this process.

Key Words: reactive oxygen species • vascular smooth muscle • differentiation • gene expression

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