A brief overview of mouse models of pulmonary arterial hypertension: problems and prospects

Abstract

Many chronic pulmonary diseases are associated with pulmonary hypertension (PH) and pulmonary vascular remodeling, which is a term that continues to be used to describe a wide spectrum of vascular abnormalities. Pulmonary vascular structural changes frequently increase pulmonary vascular resistance, causing PH and right heart failure. Although rat models had been standard models of PH research, in more recent years the availability of genetically engineered mice has made this species attractive for many investigators. Here we review a large amount of data derived from experimental PH reports published since 1996. These studies using wild-type and genetically designed mice illustrate the challenges and opportunities provided by these models. Hemodynamic measurements are difficult to obtain in mice, and right heart failure has not been investigated in mice. Anatomical, cellular, and genetic differences distinguish mice and rats, and pharmacogenomics may explain the degree of PH and the particular mode of pulmonary vascular adaptation and also the response of the right ventricle.

Fig. 1.

A: C57BL6 mouse. B: correlation between right ventricular systolic pressure (RVSP) and right ventricle (RV) to left ventricle (LV) plus septum (S) ratio (RV/LV+S) in mouse pulmonary hypertension (PH) models exposed to normoxia and hypoxia, compared with the combination of SU5416 and chronic hypoxia (SuHx) and monocrotaline (MCT)-injured rat models. C: correlation between RVSP and RV/LV+S in mouse models exposed to normoxia. Pearson coefficient 0.32, P = 0.150. D: correlation between RVSP and RV/LV+S in mouse models exposed to hypoxia. If all mouse models are included, the Pearson coefficient is 0.82, P = 0.0008. However, the correlation seems to be driven by an outlier, the IL6-OE mice (red dot). Thus, if the latter is not included in the statistical calculations, the coefficient becomes nonsignificant (r = 0.58, P = 0.057) (E). F: hematoxylin and eosin (HE)-stained lung section of a pulmonary vessel obtained from wild-type C57BL6 mice chronically exposed to ovalbumin. The mice develop severe pulmonary arterial muscularization without pulmonary hypertension. The vascular remodeling does not involve endothelial cell proliferation (G; brown staining is smooth muscle actin and blue is von Willebrand factor). F and G are reprinted from Daley et al. (2008), doi:10.1084/jem.20071008.

Fig. 2.

A: hemodynamic measurements in a normal C57BL6 mouse assessed in 2 different locations in the right ventricle. We can appreciate that a slight difference in the site of catheter insertion can cause dramatic changes in pressure recordings, even if the shape of the curve looks apparently normal. B–D: schematic representation of a pulsed-wave Doppler recording of the pulmonary artery. Animals with pulmonary hypertension show a pattern consistent with decreased pulmonary artery acceleration time (PAAT) with or without midsystolic notching (arrowhead). A bidirectional flow pattern appears when pulmonary valve insufficiency is present (D, arrow). E–H: pulsed-wave Doppler recordings from normal mouse (E), mouse overexpressing IL-6 with pulmonary hypertension (F, reproduced from Thibault HB, Kurtz B, Raher MJ, Shaik RS, Waxman A, Derumeaux G, Halpern EF, Bloch KD, Scherrer-Crosbie M. Noninvasive assessment of murine pulmonary arterial pressure: validation and application to models of pulmonary hypertension. Circ Cardiovasc Imaging 3: 157–163, 2010), normal Sprague-Dawley rat (G), and a SU5416/hypoxia exposed Sprague-Dawley rat (H). Compared with mice, rats develop a pulsed-wave Doppler pattern consisting of decreased PAAT, midsystolic notching, and bidirectional flow.

Fig. 3.

A: short-axis view obtained from a mouse overexpressing ADAM10 illustrates significant right ventricular dilatation compared with the left ventricle. B: hemodynamic measurement illustrating an increase in the right ventricular systolic pressure. C and D: HE-stained lung section illustrating occluded vessel (arrows) and normal vessels (arrowheads). E–F: immunohistochemistry of lung sections illustrating that the occluded vessels are not occluded by von Willebrand-positive endothelial cells. G: normal vessel. H: RVSP measurements in ADAM10 transgenic mouse. Light blue area marks mice that had a normal pulmonary artery pressure. Although some mice demonstrated high RVSP, the measurements were highly variable.

Fig. 4.

Mice administered SU5416 (20 mg/kg sc) once a week for 3 consecutive wk and exposed to nitrogen dilution hypoxia for 3 wk (n = 5) are compared with mice exposed only to chronic hypoxia (n = 5). Neither right ventricular hypertrophy nor RVSP were different when the 2 groups were compared (A and B); there was no difference in the hematocrit (C). Lung histology (HE staining) shows some degree of air space enlargement (D–F). Rare small vessel thrombi were observed (G). As evidenced by trichrome staining, RV fibrosis was absent (H).