A comprehensive review: the evolution of animal models in pulmonary hypertension research; are we there yet?

Abstract

Pulmonary hypertension (PH) is a disorder that develops as a result of remodeling of the pulmonary vasculature and is characterized by narrowing/obliteration of small pulmonary arteries, leading to increased mean pulmonary artery pressure and pulmonary vascular resistance. Subsequently, PH increases the right ventricular afterload, which leads to right ventricular hypertrophy and eventually right ventricular failure. The pathophysiology of PH is not fully elucidated, and current treatments have only a modest impact on patient survival and quality of life. Thus, there is an urgent need for improved treatments or a cure. The use of animal models has contributed extensively to the current understanding of PH pathophysiology and the investigation of experimental treatments. However, PH in current animal models may not fully represent current clinical observations. For example, PH in animal models appears to be curable with many therapeutic interventions, and the severity of PH in animal models is also believed to correlate poorly with that observed in humans. In this review, we discuss a variety of animal models in PH research, some of their contributions to the field, their shortcomings, and how these have been addressed. We highlight the fact that the constant development and evolution of animal models will help us to more closely model the severity and heterogeneity of PH observed in humans.

Keywords: chronic hypoxia; monocrotaline; pulmonary arterial banding; right ventricular failure.

Figure 1

TGF-β/BMPR-2 signaling axis in pulmonary hypertension (PH): a simplified schematic diagram of the TGF-β and BMPR-2 signaling pathways that underlie the pathogenesis of PH. TGF-β and BMPR-2 bind to their receptors, where TGF-β activates smad 2,3 and BMPR-2 activates smad 1,5,8. Upon phosphorylation of these smad molecules, the smad 4 molecule is activated by both pathways and translocates to the nucleus, where it promotes transcription of target genes involved in cell growth, proliferation, and apoptosis. BMPR-2: bone morphogenetic protein receptor-2; TGF-β: transforming growth factor-β; smad: small mothers against decapentaplegia. Adapted from Santibañez et al.