Rodent Models of Group 1 Pulmonary Hypertension

Abstract

World Health Organization category 1 pulmonary hypertension (PH) is a heterogeneous syndrome in which PH originates in the small pulmonary arteries and is therefore also referred to as pulmonary arterial hypertension (PAH). Common pathophysiologic features include endothelial dysfunction, excessive proliferation and impaired apoptosis of vascular cells, and mitochondrial fragmentation. The proliferation/apoptosis imbalance relates in part to activation of the transcription factors hypoxia-inducible factor-1alpha (HIF-1alpha) and nuclear factor of activated T-cells (NFAT) and apoptosis repressors, such as survivin. Perivascular inflammation, disruption of adventitial connective tissue, and a glycolytic metabolic shift in vascular cells and right ventricular myocytes also occur in PAH. There are important genetic and epigenetic predispositions to PAH. This review assesses the fidelity of existing animal models to human PAH. No single model can perfectly recapitulate the many diverse forms of PH in Category 1; however, acceptable models exist. PAH induced by monocrotaline and chronic hypoxia plus SU-5416 (CH+SU) in rats display endothelial dysfunction, proliferation/apoptosis imbalance, and develop the glycolytic metabolic profile of human PAH. Histologically, CH+SU best conforms to PAH in that it develops complex vascular lesions, including plexiform lesions. However, the monocrotaline model can be induced to manifest complex vascular lesions and does manifest the tendency of PAH patients to die of right ventricular (RV) failure. Murine models offer greater molecular certainty than rat models but rarely develop significant PH, have less right ventricular hypertrophy (RVH) and pulmonary artery (PA) remodeling, and are harder to image and catheterize. The use of high fidelity catheterization and advanced imaging (microPET-CT, high frequency echocardiography, high field strength MRI) and functional testing (treadmill) permit accurate phenotyping of experimental models of PAH. Preclinical trial design is an important aspect of testing experimental PAH therapies. The use of multiple complementary models with adequate sample size and trial duration and appropriate endpoints are required for preclinical assessment of experimental PAH therapies.