Targeted FTO knockout in endothelial cells Boosts adhesion and lowers inflammatory infiltration to alleviate pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a syndrome characterized by increased pulmonary vascular resistance and elevated pulmonary artery pressure, ultimately leading to right heart failure and even death. Increasing evidence implicates the fat mass and obesity-associated protein (FTO) in various metabolic and inflammatory pathways; however, its role in pulmonary endothelial function and PAH remains largely unexplored. In this study, we examined the effects of endothelial cell-specific FTO knockout on PAH development. Our results indicate that the absence of FTO in endothelial cells mitigates hypoxia-induced PAH. Mechanistically, FTO deletion reduces endothelial cell adhesion and inflammatory cell infiltration. Single-cell RNA sequencing revealed disruptions in key inflammatory and adhesion pathways, including TNF-α/NF-κB signaling and VCAM1 expression. These findings suggest that targeting endothelial FTO could be a novel therapeutic strategy for PAH by modulating endothelial adhesion and inflammatory responses.