Abstract
Vascular inflammation underlies the development of hypertension, and the mechanisms by which it increases blood pressure remain the topic of intense investigation. Proinflammatory factors including glucose, salt, vasoconstrictors, cytokines, wall stress, and growth factors enhance contractility and impair relaxation of vascular smooth muscle cells. These pathways share a dependence upon redox signaling, and excessive activation promotes oxidative stress that promotes vascular aging. Vascular smooth muscle cell phenotypic switching and migration into the intima contribute to atherosclerosis, while hypercontractility increases systemic vascular resistance and vasospasm that can trigger ischemia. Here, we review factors that drive the initiation and progression of this vasculopathy in vascular smooth muscle cells. Emphasis is placed on the contribution of reactive oxygen species generated by the Nox1 NADPH oxidase which produces extracellular superoxide (O(2)(•-)). The mechanisms of O(2)(•-) signaling remain poorly defined, but recent evidence demonstrates physical association of Nox1 with leucine-rich repeat containing 8 family volume-sensitive anion channels. These may provide a pathway for influx of O(2)(•-) to the cytoplasm, creating an oxidized cytoplasmic nanodomain where redox-based signals can affect both cytoskeletal structure and vasomotor function. Understanding the mechanistic links between inflammation, O(2)(•-) and vascular smooth muscle cell contractility may facilitate targeting of anti-inflammatory therapy in hypertension.