Molecular pathogenesis and current pathology of pulmonary hypertension

Abstract

Following its initial description over a century ago, pulmonary arterial hypertension (PAH) continues to challenge researchers committed to understanding its pathobiology and finding a cure. The last two decades have seen major developments in our understanding of the genetics and molecular basis of PAH that drive cells within the pulmonary vascular wall to produce obstructive vascular lesions; presently, the field of PAH research has taken numerous approaches to dissect the complex amalgam of genetic, molecular and inflammatory pathways that interact to initiate and drive disease progression. In this review, we discuss the current understanding of PAH pathology and the role that genetic factors and environmental influences share in the development of vascular lesions and abnormal cell function. We also discuss how animal models can assist in elucidating gene function and the study of novel therapeutics, while at the same time addressing the limitations of the most commonly used rodent models. Novel experimental approaches based on application of next generation sequencing, bioinformatics and epigenetics research are also discussed as these are now being actively used to facilitate the discovery of novel gene mutations and mechanisms that regulate gene expression in PAH. Finally, we touch on recent discoveries concerning the role of inflammation and immunity in PAH pathobiology and how they are being targeted with immunomodulatory agents. We conclude that the field of PAH research is actively expanding and the major challenge in the coming years is to develop a unified theory that incorporates genetic and mechanistic data to address viable areas for disease modifying drugs that can target key processes that regulate the evolution of vascular pathology of PAH.

Keywords: Animal models of disease; BMPR2; Endothelial cells; Epigenetics; Genetics; Inflammation; Lung pathology; Pulmonary arterial hypertension; Right heart failure; Vascular biology; Vascular smooth muscle cells.