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

Clinical observations have suggested an association between alkylating agents-based chemotherapy and pulmonary arterial hypertension (PAH). The Fanconi anemia (FA) pathway, principal mechanism for resolving alkylating agent-induced DNA damage, has been implicated in this process. To establish the interplay among FA pathway, DNA damage and PAH. A knockout-first mouse model for FA complementation group L (Fanclkf/kf) and an adeno-associated virus 9-mediated Fancl overexpression (AAV-Fancl) model were used. Lung specimens, pulmonary arterial endothelial cells (PAECs) from patients with PAH, and primarily cultured pulmonary microvascular endothelial cells (PMVECs) from wild-type and Fanclkf/kf mice were analyzed. Data analysis on lung single-cell RNA sequencing datasets revealed significant downregulation of FANCL in endothelial cells from idiopathic PAH (IPAH) patients, a finding consistently validated in both clinical samples (lung specimens and PAECs) 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 (BMP) signaling coupled with hyperactivated transforming growth factor beta (TGF-β) pathways in PMVECs from Fanclkf/kf mice. Importantly, this imbalance was fully restored in PMVECs from AAV-Fancl-treated mice. 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.