A Novel Rat Model for Group 2 Pulmonary Hypertension by Total Pulmonary Vein Banding: Multi-Omics Insights into Pathophysiological Mechanisms

OBJECTIVES Group 2 pulmonary hypertension (PH) remains a highly morbid disease, yet no specific therapy exists. We sought to determine whether total pulmonary vein banding (TPVB) in rats could reliably display the clinical features of group 2 PH, and sought to investigate potential molecular and cellular determinants associated with disease progression. METHODS Four-week-old Sprague-Dawley rats were randomized to receive TPVB (n=18) or sham procedure (n=18). Serial hemodynamic and histological assessments were performed at post-TPVB week 1, 4, and 8. At each time point, 12 rats (6 in TPVB 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 PH development. RESULTS Comparing to the sham group, rats in the TPVB group developed PH after surgery. Mild to severe progression of PH was observed in the TPVB group from post-surgery week 1 to 8, including higher right ventricular systolic pressure (P < 0.001), impaired right ventricle (RV)-pulmonary artery coupling (P < 0.001), decreased tricuspid annular plane systolic excursion (P < 0.001) and RV fractional area change (P < 0.001). Slc2a1 was identified as a hub gene upregulated in the lungs, which was enriched in the perivascular macrophages and associated with disease progression. CONCLUSIONS Rodent model of TPVB provides a useful platform for modeling PV-congestion severe group 2 PH. Slc2a1 is a key regulator of perivascular macrophage infiltration, driving the disease progression. Targeting Slc2a1-mediated perivascular inflammation might have a therapeutic potential.