Abstract Body (Do not enter title and authors here): We are seeking to elucidate the endothelial fatty acid metabolism role for obstructive vascular remodeling in the pathogenesis of PAH.

In this study, we bred a severe mouse model of PH Egln1^Tie2Cre mice with Fabp45^-/- mice to generate Egln1^Tie2Cre/Fabp45^-/- mice. We applied single-cell RNA sequencing (scRNA-seq) to profile the pulmonary cells in Egln1^Tie2Cre mice and Egln1^Tie2Cre/Fabp45^-/- mice. Human hPAEC from idiopathic PAH patients and healthy donors were used to measure fatty acid-binding protein 4 and 5 (FABP4 and FABP5) expression via sc-RNA seq and spatial transcriptomics. siRNA-mediated knockdown of FABP4 and FABP5 and lentivirus-mediated FABP4 and 5 overexpression were performed to study cell proliferation, apoptosis, and glycolysis.

Our scRNA-seq analysis demonstrated that both FABP4 and 5 were highly induced in the ECs of Egln1^Tie2Cre mice. PAECs from IPAH patients also showed higher expression of FABP4 and 5. Knockdown of FABP4-5 reduced EC proliferation, starvation-induced Caspase 3/7 activity, and glycolysis. Overexpression of FABP4-5 promoted EC glycolysis and proliferation. Genetic deletion of Fabp4 and 5 in Egln1^Tie2Cre mice exhibited a reduction of RVSP, RV hypertrophy, and reduction of EC glycolysis gene programming compared to Egln1^Tie2Cre mice.

In conclusion, we found that FABP4 and 5 control EC glycolysis and contribute to the development of PAH.