Interleukin-35 alleviates pulmonary arterial hypertension by suppressing the VEGFA/VEGFR2 signaling pathway.

Pulmonary arterial hypertension (PAH) is a serious circulatory disorder defined by elevated pulmonary arterial pressure (PAP) with normal pulmonary capillary wedge pressure (PCWP), driven by pathological remodeling of pulmonary arterioles. If left untreated, it can lead to severe health complications and death. Current treatments, such as endothelin receptor antagonists and phosphodiesterase-5 inhibitors, prostacyclin analogs, and soluble guanylate cyclase stimulators-these agents relieve symptoms, improve exercise capacity, and delay disease progression but do not target the underlying vascular pathology. Because these therapies fail to improve long-term prognosis, they impose a heavy burden on patients, families, and society. Thus, there is an urgent need to develop new therapeutic agents that can treat PAH more effectively. Interleukin-35 (IL-35), which is primarily produced by regulatory T cells, is a potent molecule exhibiting significant anti-inflammatory and immunomodulatory properties. Recent research suggests that IL-35 shows promise as a novel therapeutic agent for PAH. However, the precise mechanism by which IL-35 influences pulmonary hypertension remains to be elucidated through further experimentation. To address this, we established animal and cellular models and analyzed molecular, functional, and structural changes using western blotting, PAP measurements, flow cytometry, EdU staining, scratch assay, blood biochemistry, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), hematoxylin and eosin (H&E), Immunohistochemistry (IHC) and Masson's trichrome staining. Our results suggest that IL-35 alleviates PAH-induced inflammation, apoptosis, and smooth muscle cell proliferation, reduces PAP, and restores vascular remodeling, thereby mitigating both structural and functional damage in PAH.