A Cross-Species and Sex-Specific Meta-Analysis of Transcriptomic Studies of Pulmonary Hypertension

Pulmonary hypertension (PH) is a life-threatening disease characterized by pulmonary vascular remodeling and right ventricle dysfunction. Among the five PH groups, group 1 pulmonary arterial hypertension (PAH) is a particularly serious condition characterized by a poor prognosis. PAH can occur in idiopathic, associated, and heritable forms, and has a notable female predominance. A number of in vivo PH models in rodents, together with in vitro cultured vascular cells such as pulmonary arterial pulmonary arterial (PA) endothelial cells and PA smooth muscle cells derived from patients with PAH, have been widely used to reproduce the pathological disease features. To systematically evaluate the in vivo and in vitro efficacy of the existing PH model systems, publicly available whole-transcriptome data from humans and rodents were collected and analyzed. Subgroups of the Schistosoma-induced female PH model in mice and the male chronic hypoxia PH model in rats correlated well with human heritable PAH and idiopathic PAH lungs, respectively. An SU5416 chronic hypoxia PH model is well connected to the decompensated right ventricles of human PAH. Sex dimorphisms have been observed in PAH-derived PA endothelial cells and PA smooth muscle cells, independent of gonadal hormones. We conducted, for the first time, a meta-cohort and cross-species comparative study and identified optimal in vivo and in vitro PH model systems that recapitulate certain aspects of human PH, which could provide novel insights into new therapeutic avenues in PH.