Experimental animal models of pulmonary hypertension: Development and challenges

Abstract

Pulmonary hypertension (PH) is a severe, progressive vascular disorder characterized by elevation in pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), finally leading to right heart failure and death. During the rise in PAP and PVR, vascular remodeling is accompanied by accumulation of pulmonary artery smooth muscle cells (PASMCs), endothelial cells (ECs), fibroblasts, myofibroblasts and pericytes in pulmonary arterial wall, which leads to thickening of the inner and outer linings of blood vessels, loss and obstructive remodeling of the pulmonary vascular bed and perivascular inflammation. 1-3 Associated with multiple primary causes, PH encompasses a group of clinical entities. According to the latest classification proposed by the Sixth World Symposium on PH, the disease can develop due to pulmonary arterial disorder, left heart disease, lung disease or hypoxia, chronic thromboembolic disease and other unclear or multifactorial mechanisms. 4 Though current treatments can improve clinical symptoms and hemodynamic abnormality to some extent, it is difficult to target pulmonary vascular remodeling and

Animals in Respiratory Research

“…Exposure to 10–12% oxygen (hypoxia) for 3–5 weeks is a reproducible method to increase right ventricular systolic pressure, followed by remodeling of the pulmonary vasculature in mice [ 145 ]. When combined with the VEGF receptor antagonist Sugen 5416, the hypoxia treatment is more effective.…”

“…Since other respiratory diseases also cause vascular remodeling, exposure to cigarette smoke (in COPD) and bleomycin (in IPF) can also be used to induce PH [ 146 ]. Surgical procedures such as left pneumonectomy or pulmonary artery binding also increase right ventricular pressure [ 145 ].…”

Pericytes: The lung-forgotten cell type

“…PH manifests with symptoms including dyspnoea, fatigue, dizziness, angina, irregular heartbeat, and oedema and is clinically defined as abnormally high pressure in the pulmonary artery and right ventricle of the heart, i.e., above 25 mmHg at rest according to current guidelines ( Simonneau et al, 2019 ). A number of pathologies can lead to PH, with five types of PH defined by the World Health Organization: pulmonary arterial disease, left heart disease, lung disease, chronic thromboembolic disease, and unclear or multifactorial mechanisms ( Wu X. H. et al, 2022 ). Of these, Type 1 (PAH) results from endothelial cell dysfunction, leading to inflammation, occlusive remodelling of the small pulmonary arteries, accumulation of vascular smooth muscle cells, and fibrosis; these processes ultimately lead to the formation of plexiform lesions in the pulmonary arteries and right ventricular failure ( Liu et al, 2022 ).…”

“…A number of animal models of PH have been developed in an effort to recapitulate the mechanistic origins and pathophysiology of clinical PH. These animal models (predominantly established in rats and mice) can be defined according to the method of model induction: non-invasive, invasive, and genetically modified models ( Wu H. et al, 2022 ). However, as the molecular mechanisms of clinical PH are not fully understood, particularly in the case of idiopathic PAH, these models cannot be relied upon to explain early events in PH induction and progression.…”

“…Non-invasive models of PH in rodents are primarily driven by chronic hypoxia (CH), treatment with the VEGFR-2 antagonist Sugen 5,416 (SU5416; semaxanib), or exposure to the macrocyclic pyrrolizidine alkaloid monocrotaline ( Wu H. et al, 2022 ). In CH-induced PH rats, exposure to 10% oxygen for a period of 3–4 weeks results in pulmonary arterial remodelling and endothelial cell dysfunction ( Wu et al, 2020 ); similar CH exposure in mice results in a milder phenotype ( West and Hemnes, 2011 ).…”