Establishment of mouse models for severe pulmonary hypertension through 'double-hit' strategies.

Abstract

Mouse models are crucial for understanding pulmonary hypertension (PH) mechanisms and developing therapies, but existing mouse models under hypoxia only exhibit mild PH. To address this, we established a double-hit model combining unilateral pneumonectomy (LPx) or left pulmonary artery ligation (LPAL) with hypoxia exposure in C57BL/6 mice. Our detailed haemodynamic and histological evaluations post-surgery demonstrated pronounced elevations in right ventricular systolic pressure (RVSP) (LPAL: 41.1±4.63mmHg, P=0.005; LPx: 38.4±2.95mmHg, P=0.002; Sham: 32.1±2.21mmHg) and pulmonary vascular wall thickness (LPAL: 56.9±3.34%, P=0.02; LPx: 54.3±4.65%, P=0.04; Sham: 44.8±3.76%) compared to hypoxia-exposed sham-operated controls, reflecting a more severe PH phenotype. These novel models, which exhibit haemodynamic alterations akin to the established hypoxia with SU5416-induced PH model as per published data, could offer a substantial contribution to future PH research and therapeutic development.