Receptor Signaling in Pulmonary Arterial Hypertension

Abstract

Research on the molecular basis of pulmonary arterial hypertension (PAH) caused by perturbations in receptor signaling in vascular endothelial and smooth muscle cells is beginning to yield novel approaches to future therapies for this disease. This chapter focuses on recent findings of the role of two different receptors – NOTCH3 and bone morphogenetic protein (BMP) receptor (BMPR) type 2 (BMPR-2) – in regulating vascular smooth muscle cell and endothelial cell behavior and phenotype, and discusses the potential role of ligand–receptor signaling in the genesis of PAH. Changes in the structure, function, and integrity of blood vessels are necessary for the pathogenesis of many diseases, including PAH. This disease is characterized by structural remodeling of small pulmonary arteries and arterioles, due to vessel thickening and luminal occlusion by vascular smooth muscle cell and endothelial proliferation. The vasculopathy seen in PAH is progressive, diffuse, and eventually results in obliteration of the distal pulmonary arterial tree. From a clinical point of view, PAH manifests itself as sustained elevation in pulmonary arterial pressures and pulmonary vascular resistance, leading to right-sided heart failure and death. Although several stimuli and conditions, such as hypoxia, fenfluoramine ingestion, collagen vascular disease, portal hypertension, and intracardiac left-to-right shunting, are associated with this disease [3], the exact mechanism of how the lung remodels its vascular architecture in the pulmonary artery bed in PAH is not known. Increasing evidence suggests that two types of receptors, NOTCH and BMPR, may each play an important role in the genesis of this disease. This emerging body of literature lays the groundwork for designing therapy based on the basic biology of the pulmonary vascular wall.