Mechanisms of disease: pulmonary arterial hypertension

Abstract

In the past decade or so, our understanding of pulmonary arterial hypertension has undergone a paradigm shift. In this article, Dr Schermuly and colleagues discuss the known molecular mechanisms of the pathogenesis of this disease, and highlight the molecular technologies that are currently being used to further our understanding of these disease processes.

Abstract

Our understanding of, and approach to, pulmonary arterial hypertension has undergone a paradigm shift in the past decade. Once a condition thought to be dominated by increased vasoconstrictor tone and thrombosis, pulmonary arterial hypertension is now seen as a vasculopathy in which structural changes driven by excessive vascular cell growth and inflammation, with recruitment and infiltration of circulating cells, play a major role. Perturbations of a number of molecular mechanisms have been described, including pathways involving growth factors, cytokines, metabolic signaling, elastases, and proteases, that may underlie the pathogenesis of the disease. Elucidating their contribution to the pathophysiology of pulmonary arterial hypertension could offer new drug targets. The role of progenitor cells in vascular repair is also under active investigation. The right ventricular response to increased pressure load is recognized as critical to survival and the molecular mechanisms involved are attracting increasing interest. The challenge now is to integrate this new knowledge and explore how it can be used to categorize patients by molecular phenotype and tailor treatment more effectively.

Key Points

• Pulmonary hypertension is a progressive disease of various origins, which has a poor prognosis and affects, in its different forms, more than 100 million people worldwide

• Pulmonary arterial hypertension (PAH) is now considered to be a vasculopathy in which structural changes driven by excessive vascular cell growth and inflammation have a major role

• A number of proproliferative signaling pathways involving growth factors, cytokines, metabolic signaling, and elastases and proteases have been identified in the pathophysiology of PAH

• Clinical studies with tyrosine kinase inhibitors, serotonin antagonists, and soluble guanylate cyclase stimulators are underway in patients with PAH

• The benefits of progenitor cells for vascular repair in PAH are under active investigation

• The right ventricular response to increased pressure load is recognized as critical to survival in patients with PAH, and strategies for preserving myocardial function are increasingly attracting interest