Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure

Abstract

At present, six groups of chronic pulmonary hypertension (PH) are described. Among these, group 1 (and 1') comprises a group of diverse diseases termed pulmonary arterial hypertension (PAH) that have several pathophysiological, histological, and prognostic features in common. PAH is a particularly severe and progressive form of PH that frequently leads to right heart failure and premature death. The diagnosis of PAH must include a series of defined clinical parameters, which extend beyond mere elevations in pulmonary arterial pressures and include precapillary PH, pulmonary hypertensive arteriopathy (usually with plexiform lesions), slow clinical onset (months or years), and a chronic time course (years) characterized by progressive deterioration. What appears to distinguish PAH from other forms of PH is the severity of the arteriopathy observed, the defining characteristic of which is "plexogenic arteriopathy." The pathogenesis of this arteriopathy remains unclear despite intense investigation in a variety of animal model systems. The most commonly used animal models ("classic" models) are rodents exposed to either hypoxia or monocrotaline. Newer models, which involve modification of classic approaches, have been developed that exhibit more severe PH and vascular lesions, which include neointimal proliferation and occlusion of small vessels. In addition, genetically manipulated mice have been generated that have provided insight into the role of specific molecules in the pulmonary hypertensive process. Unfortunately, at present, there is no perfect preclinical model that completely recapitulates human PAH. All models, however, have provided and will continue to provide invaluable insight into the numerous pathways that contribute to the development and maintenance of PH. Use of both classic and newly developed animal models will allow continued rigorous testing of new hypotheses regarding pathogenesis and treatment. This review highlights progress that has been made in animal modeling of this important human condition.

The Effects of a Novel Endothelin Receptor Antagonist, Macitentan, on Right Ventricular Substrate Utilization and Function in a Sugen5416/Hypoxia Rat Model of Severe Pulmonary Artery Hypertension

“…Monocrotaline (MCT)-induced PAH is one of the oldest and most widely used models of PAH (Stenmark et al, 2009). MCT is a naturally occurring pyrrolizidine alkaloid toxin found extracted from the plant species Crotalaria (Nishimura et al, 2002;Stenmark et al, 2009).…”

“…MCT is a naturally occurring pyrrolizidine alkaloid toxin found extracted from the plant species Crotalaria (Nishimura et al, 2002;Stenmark et al, 2009).…”

“…PAH is induced in rats by administering one single injection of the toxin, making it affordable and technically simple (Stenmark et al, 2009). The exact mechanism by which MCT induces PAH is unclear however, it has been suggested that direct endothelial damage is the initiating event (Stenmark et al, 2009).…”

“…The exact mechanism by which MCT induces PAH is unclear however, it has been suggested that direct endothelial damage is the initiating event (Stenmark et al, 2009). MCT causes an increase in PAP and vascular remodeling characterized by disorganized endothelial proliferation and medial hypertrophy (Stenmark et al, 2009).…”

Egr-1 Expression During Neointimal Development in Flow-Associated Pulmonary Hypertension

“…Several animal models have been described to investigate the pathogenesis of PAH. 6 The toxic alkaloid monocrotaline model is a commonly used experimental model of pulmonary hypertension. However, in this model neointimal lesions, typical for irreversible PAH, 3 are not seen.…”