A novel rat model for group 2 pulmonary hypertension by total pulmonary vein banding: Multi-omics insights into pathophysiological mechanisms.

Abstract

Group 2 pulmonary hypertension remains a highly morbid disease, yet no specific therapy exists. We sought to determine whether total pulmonary vein banding in rats could reliably display the clinical features of group 2 pulmonary hypertension and sought to investigate potential molecular and cellular determinants associated with disease progression. Four-week-old Sprague-Dawley rats were randomized to receive total pulmonary vein banding (n = 18) or sham procedure (n = 18). Serial hemodynamic and histological assessments were performed at post-total pulmonary vein banding weeks 1, 4, and 8. At each time point, 12 rats (6 in total pulmonary vein banding vs 6 in sham group) underwent harvest for lung sectioning and transcriptomic and proteomic analysis. Weighted gene coexpression and Bayesian networks were used to explore the top hub gene associated with pulmonary hypertension development. Compared with the sham group, rats in the total pulmonary vein banding group developed pulmonary hypertension after surgery. Mild to severe progression of pulmonary hypertension was observed in the total pulmonary vein banding group from postsurgery week 1 to 8, including higher right ventricular systolic pressure (P < .001), impaired right ventricle-pulmonary artery coupling (P < .001), decreased tricuspid annular plane systolic excursion (P < .001), and right ventricle fractional area change (P < .001). Slc2a1 was identified as a hub gene upregulated in the lungs, which was enriched in the perivascular macrophages and associated with disease progression. This rodent model of total pulmonary vein banding provides a useful platform for modeling pulmonary vein congestion severe group 2 pulmonary hypertension. Slc2a1 is a key regulator of perivascular macrophage infiltration, driving the disease progression. Targeting Slc2a1-mediated perivascular inflammation might have a therapeutic potential.