Type 2 inflammation mediates pulmonary vascular remodeling in a murine model of SSc-PAH

In pulmonary arterial hypertension (PAH), remodeling of lung vessels results in heightened pulmonary vascular resistance, subsequently causing hypertrophy and eventual failure of the right ventricle. PAH can manifest in patients afflicted with systemic sclerosis (SSc) as a potentially fatal complication. Immunological mechanisms are pivotal in remodeling processes of the pulmonary vasculature, as evidenced in the Fos-related antigen-2 (Fra-2) overexpressing mouse model, which mimics SSc-PAH. Our study aims to ascertain whether type 2 inflammation promotes remodeling of the pulmonary vasculature in Fra-2 transgenic (TG) mice and whether it is concomitant with vascular hyperresponsiveness, a key aspect of PAH pathology. In isolated perfused and ventilated lungs of Fra-2 overexpressing mice, mean pulmonary arterial pressure as well as vascular responsiveness to serotonin and hypoxic ventilation were elevated compared to wild-types. Analogously, contraction of isolated intrapulmonary arteries was heightened in Fra-2 TG mice. In human pulmonary artery smooth muscle cells overexpressing Fra-2, administration of IL-13 led to elevated intracellular Ca²⁺ levels. Transcriptomic analyses further revealed aberrations in genes related to type 2 immune response and vascular smooth muscle contraction in Fra-2 TG mice. <italic>In vivo</italic> data in Fra-2 overexpressing mice demonstrated that a type 2-specific therapeutic approach with anti-IL-13 blocking antibodies alleviated pulmonary vascular remodeling akin to budesonide treatment. Our findings reveal the significance of type 2 inflammation in driving SSc-PAH-associated remodeling and hyperresponsiveness of the pulmonary vasculature. CT & GK contributed equally.