FOXC1 drives pulmonary arterial endothelial cell dysfunction and vascular remodeling through transcriptional activation of MACC1.

BACKGROUND

Pulmonary arterial hypertension (PAH) is a progressive vascular disorder characterized by pulmonary vascular remodeling and endothelial dysfunction. Although several molecular regulators have been implicated in PAH pathogenesis, the key transcriptional networks governing these processes remain incompletely understood. This study aimed to investigate the role of the transcription factor forkhead box C1 (FOXC1) in PAH development and evaluate its potential as a therapeutic target.

METHODS

Bioinformatic analysis of single-cell RNA sequencing data (GSE293580) was performed to identify critical regulatory hubs in PAH endothelial cells. FOXC1 expression was validated in serum samples from patients with PAH and in multiple experimental PAH models, including hypoxia-, Sugen5416/hypoxia (SuHx)-, and monocrotaline (MCT)-induced models. The therapeutic effects of FOXC1 inhibition were evaluated using adeno-associated virus serotype 6 (AAV6)-mediated knockdown in vivo. In vitro functional assays using human pulmonary artery endothelial cells (hPAECs), together with chromatin immunoprecipitation quantitative PCR (ChIP-qPCR), were performed to elucidate the underlying molecular mechanisms.

RESULTS

FOXC1 was identified as a central transcriptional hub in endothelial cells from patients with idiopathic PAH. Circulating FOXC1 levels were positively correlated with mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) in patients with PAH. In vivo, FOXC1 knockdown significantly alleviated right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and pulmonary vascular remodeling in both hypoxia- and SuHx-induced PAH models. Mechanistically, FOXC1 directly bound to the promoter region of MACC1 and transcriptionally activated its expression. Silencing MACC1 markedly attenuated the enhanced proliferation, migration, and angiogenic responses induced by FOXC1 overexpression in hPAECs.

CONCLUSION

The FOXC1/MACC1 regulatory axis contributes to endothelial dysfunction and pulmonary vascular remodeling in PAH. Targeting this pathway may represent a potential therapeutic strategy for PAH treatment.