Idiopathic pulmonary arterial hypertension

Abstract

Despite improved understanding of the pathobiology of pulmonary arterial hypertension (PAH), it remains a severe and progressive disease, usually culminating in right heart failure, significant morbidity and early mortality. Over the last decade, some major advances have led to substantial improvements in the management of PAH. Much of this progress was pioneered by work in animal models. Although none of the current animal models of pulmonary hypertension (PH) completely recapitulate the human disease, they do provide insight into the cellular pathways contributing to its development and progression. There is hope that future work in model organisms will help to define its underlying cause(s), identify risk factors and lead to better treatment of the currently irreversible damage that results in the lungs of afflicted patients. However, the difficulty in defining the etiology of idiopathic PAH (IPAH, previously known as primary pulmonary hypertension) makes this subset of the disease particularly difficult to model. Although there are some valuable existing models that are relevant for IPAH research, the area would value from the development of new models that more closely mimic the clinical pathophysiology of IPAH.

Transient Receptor Potential Channel 4 Encodes a Vascular Permeability Defect and High-Frequency Ca2+ Transients in Severe Pulmonary Arterial Hypertension

“…11,13,17,18,20,21,26 Vascular remodeling of the vessel media and intima occurs heterogeneously along arteries and arterioles in this disease. 13,34 Notably, medial thickening is seen along arteries and arterioles with distal extension of smooth muscle into typically nonmuscularized segments in PAH.…”

“…4,11,16,18,22 Of the various models of PAH and hypoxic hypertension, only the Sugen/hypoxia model of severe pulmonary hypertension reproduces the characteristic endothelial cell remodeling of small arterioles and mortality seen in human PAH. 29 Within the lung, endothelial cells from conduit arteries and microvessels exhibit distinct phenotypic heterogeneity and embryonic origin.…”

Role of Notch Signaling in Pulmonary Hypertension

“…Chronic Hypoxia exposure of mice is characterized by minimal vascular remodeling, depicted mainly by medial hypertrophy and no or negligible endothelial damage or neointima formation [148,151]. Hence, the significant decrease observed in MCT model for some Notch receptors (Notch4 and Notch1) are not seen here.…”

“…CH mouse model has been used to investigate the role of NO pathway, reactive oxygen species (ROS) and cytoskeletal architecture in development of PH [77,152,153]. The main limitation of this model is that CH induced PH in mice and rats is reversed once the animals are exposed to normal oxygen concentrations [148]. MCT--injected rats for 2 weeks at the second day of MCT injection [48].…”

Reversibility of the monocrotaline pulmonary hypertension rat model

“…The active MCT pyrrole is pneumotoxic and damages the pulmonary artery endothelial cells (PAECs), which leads to a disturbed barrier function [4]. Other features of MCT-induced pulmonary vascular remodelling are arterial medial hyperplasia of axial arteries, interstitial oedema, adventitial inflammation, haemorrhage and, eventually, fibrosis [1,2,5,6]. As a result, pulmonary vascular resistance (PVR) increases and the right ventricle compensates by hypertrophy and eventually fails [7,8].…”