Deficient FANCL Predisposes to Endothelial Damage: A New Therapeutic Target for Pulmonary Hypertension

Rationale Clinical observations have suggested an association between alkylating agent–based chemotherapy and pulmonary arterial hypertension (PAH). The Fanconi anemia (FA) pathway, the principal mechanism for resolving alkylating agent–induced DNA damage, has been implicated in this process. Objectives To establish the interplay among the FA pathway, DNA damage, and PAH. Methods A knockout-first mouse model for FA complementation group L (Fanclkf/kf) and an adenovirus-associated virus 9–mediated Fancl overexpression (AAV-Fancl) model were used. Lung specimens, pulmonary arterial endothelial cells from patients with PAH, and primarily cultured pulmonary microvascular endothelial cells (PMVECs) from wild-type and Fanclkf/kf mice were analyzed. Measurements and Main Results Data analysis on lung single-cell RNA-sequencing datasets revealed significant downregulation of FANCL in endothelial cells from patients with idiopathic PAH, a finding consistently validated in both clinical samples (lung specimens and pulmonary arterial endothelial cells) and the monocrotaline-induced PAH rat model. Notably, Fanclkf/kf mice developed spontaneous PAH and showed heightened susceptibility to alkylating agent (mitomycin C)-induced PAH, characterized by severe DNA damage and apoptosis in PMVECs. These pathological phenotypes were rescued through Fancl gene supplementation via AAV-Fancl or pharmacological intervention with the DNA damage protector amifostine. Mechanistically, transcriptomic profiling combined with functional validation demonstrated a suppressed bone morphogenetic protein signaling coupled with hyperactivated transforming growth factor-β pathways in PMVECs from Fanclkf/kf mice. Importantly, this imbalance was fully restored in PMVECs from AAV-Fancl–treated mice. Conclusions Deficient Fancl plays a key role to promote PAH, and targeted rescue of Fancl could be a novel effective strategy for the treatment of PAH.