ABSTRACT
Pulmonary hypertension (PH) is a progressive lung disease characterized by persistent pulmonary vasoconstriction. Another well-recognized characteristic of PH is the muscularization of peripheral pulmonary arteries. This pulmonary vasoremodeling manifests in medial hypertrophy/hyperplasia of smooth muscle cells (SMCs) with possible neointimal formation. The underlying molecular processes for these two major vascular responses remain not fully understood. On the other hand, a series of very recent studies have shown that the increased reactive oxygen species (ROS) seems to be an important player in mediating pulmonary vasoconstriction and vasoremodeling, thereby leading to PH. Mitochondria are a primary site for ROS production in pulmonary artery (PA) SMCs, which subsequently activate NADPH oxidase to induce further ROS generation, i.e., ROS-induced ROS generation. ROS control the activity of multiple ion channels to induce intracellular Ca2+ release and extracellular Ca2+ influx (ROS-induced Ca2+ release and influx) to cause PH. ROS and Ca2+ signaling may synergistically trigger an inflammatory cascade to implicate in PH. Accordingly, this paper explores the important roles of ROS, Ca2+, and inflammatory signaling in the development of PH, including their reciprocal interactions, key molecules, and possible therapeutic targets.
