Role of Subplasmalemmal Mitochondria in Angiotensin II–Mediated Contraction

Nearly 2 decades after the seminal work by Sundaresan et al,1 which established the requirement of hydrogen peroxide (H2O2) during platelet-derived growth factor–initiated signal transduction in vascular smooth muscle cells (VSMCs), it is now well accepted that enzymatically generated reactive oxygen species (ROS) play pivotal roles as signaling molecules during both physiological and pathological conditions. In fact, virtually all cellular programs in VSMCs including differentiation,2 growth,3 contraction,4 and migration5 use ROS as a part of their signaling machinery. Article, see p 1013 ROS are produced from a sequential 1- or 2-electron reduction of molecular oxygen. Mitochondria are classically linked to ROS generation, which are formed as a by-product of mitochondrial respiration.6 In addition, VSMCs contain a variety of other sources of ROS, including xanthine oxidase,7 lipoxygenases,8 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases.9 The NADPH oxidase multienzymatic complexes are major sources of superoxide (O2·–) and H2O2, which in this cell type have been shown to participate in the signaling pathways of growth and differentiation and in the mediation of the effects of vasoactive peptides such as angiotensin II (AngII).10 In particular, the Nox1-based NADPH oxidase is activated downstream of the AngII type 1 receptor in VSMCs,11 where it is required for AngII-induced hypertension …