Animal models of pulmonary hypertension: Getting to the heart of the problem

Abstract

Despite recent therapeutic advances, pulmonary hypertension (PH) remains a fatal disease due to the development of right ventricular (RV) failure. At present, no RV-targeted therapies are available, and RV function is not widely considered in the preclinical assessment of new therapeutics. Several small animal models are used in the study of PH, including the classic models of exposure to either hypoxia or monocrotaline, newer combinational and genetic models, and pulmonary artery banding, a surgical model of pure RV pressure overload. These models recapitulate selected features of the structural remodelling and functional decline seen in patients and have provided valuable insight into the pathophysiology of RV failure. However, significant reversal of remodelling and improvement in RV function remains a therapeutic obstacle. Emerging animal models will provide a deeper understanding of the mechanisms governing the transition from adaptive remodelling to a failing RV, aiding the hunt for druggable molecular targets.

Cannabidiol Improves Antioxidant Capacity and Reduces Inflammation in the Lungs of Rats with Monocrotaline-Induced Pulmonary Hypertension

“…We used this model because it well reflects changes in human’s PH, and causes selective damage to pulmonary circulation. The MCT model is an inflammatory model that has been used in experimental studies with drugs already used in the standard treatment of PH [ 18 ].…”

“…Due to the current trend of using polypharmacological approaches in PH treatment, together with the proven beneficial effects of CBD in various PH models as a consequence of its antioxidant and anti-inflammatory properties, the aim of the study was to evaluate the effect of CBD on the selected parameters of oxidative stress and inflammation in the lungs of rats with MCT-induced PH. Although previous studies suggest that CBD may have anti-inflammatory potential in the mouse model of Sugen-hypoxia-induced PH [ 16 ], it has been recently reported that the Sugen-hypoxia model is not preferable in mice, since they display very modest vascular remodeling compared to rats [ 17 , 18 , 19 ]. In this respect, both pulmonary vascular remodeling and PH are reversible, and no characteristic perivascular infiltration of monocytes/macrophages is observed [ 17 , 18 , 19 ].…”

“…Although previous studies suggest that CBD may have anti-inflammatory potential in the mouse model of Sugen-hypoxia-induced PH [ 16 ], it has been recently reported that the Sugen-hypoxia model is not preferable in mice, since they display very modest vascular remodeling compared to rats [ 17 , 18 , 19 ]. In this respect, both pulmonary vascular remodeling and PH are reversible, and no characteristic perivascular infiltration of monocytes/macrophages is observed [ 17 , 18 , 19 ]. The MCT-induced PH model in rats is more recommended because it particularly shows the role of inflammation in the development of PH, and allows the development of damage to pulmonary vessel endothelia with the characteristic perivasculitis [ 18 ].…”

“…In this respect, both pulmonary vascular remodeling and PH are reversible, and no characteristic perivascular infiltration of monocytes/macrophages is observed [ 17 , 18 , 19 ]. The MCT-induced PH model in rats is more recommended because it particularly shows the role of inflammation in the development of PH, and allows the development of damage to pulmonary vessel endothelia with the characteristic perivasculitis [ 18 ].…”

How good are our models of cardiovascular disease?

“…However, there are still no therapies targeted to right ventricular failure, and right ventricular function is not always addressed in the preclinical evaluation of new therapeutics. Dignam et al (2021) describe several small animal models used to study pulmonary hypertension, including classical models involving exposure to hypoxia or monocrotaline, newer combinational and genetic models and a surgical model of pulmonary artery banding to produce right ventricular pressure overload. Recapitulation by these models of clinical features (structural remodelling and functional decline) has provided valuable insight into the pathophysiology of right ventricular failure.…”