Pathogenic Mechanisms of Pulmonary Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance, which results in a progressive, debilitating, and often fatal disease. Understanding normal anatomic and physiologic principles of the pulmonary circulation is key to recognizing the derangements that characterize pulmonary arterial hypertension. Pathogenic features leading to pulmonary arterial hypertension include sustained vasoconstriction, pulmonary vascular remodeling, endothelial dysfunction, in situ thrombosis, and plexiform arteriopathy. Numerous cellular and molecular mechanisms have been demonstrated to contribute to these pathogenic features, involving often complex interactions. An imbalance of vasoactive mediators, increased growth factor activity, cellular microparticle release, inflammation, functional changes in membrane receptors and ion channels, and altered cellular signaling pathways have all been implicated in the pathogenesis of pulmonary arterial hypertension. Additionally, a genetic basis for this disease has been established, most clearly illustrated by mutations of bone morphogenetic protein receptor type 2 which have been recognized in a subset of PAH patients. This chapter will provide an overview of the current evidence regarding the major pathogenic mechanisms of pulmonary arterial hypertension, along with cellular and molecular mechanisms which have been associated with this disease.