Alkylating Agent-Induced FANCL Impairment Damages Pulmonary Arterial, Venous, and Microvascular Endothelial Cells and Predisposes to PAH/PVOD.

Alkylating chemotherapies such as mitomycin C (MMC) and cisplatin (CDDP) are associated with pulmonary arterial hypertension (PAH) with pulmonary veno-occlusive disease (PVOD) features, yet the underlying mechanisms remain unclear. Using established MMC and newly developed CDDP rat models, we found that both agents induced PAH/PVOD, as evidenced by elevated right ventricular systolic pressure, pulmonary arterial, venous and microvascular remodeling, and right ventricular dysfunction, with MMC causing more severe pathology. In cultured pulmonary arterial, venous, and microvascular endothelial cells, MMC and CDDP induced elevated DNA damage, apoptosis, and endothelial-to-mesenchymal transition, together with impaired angiogenic capacity, proliferation, and barrier junction. These phenotypical changes were accompanied by conserved Fanconi anemia complementation group L (FANCL) downregulation. FANCL deficiency in mice drove spontaneous and exacerbated CDDP‑induced PAH/PVOD, whereas AAV‑mediated FANCL rescue or treatment with a DNA protector, amifostine, significantly attenuated the disease pathogenesis in mouse and rat models. Collectively, this study establishes a novel CDDP‑induced rat model, identifies a conserved FANCL-DNA damage-endothelial dysfunction mechanistic axis underlying PAH/PVOD induced by MMC or CDDP, and highlights FANCL rescue and DNA damage inhibition as potential therapeutic strategies for this severe form of pulmonary vascular disease.