Single-Cell and Spatial Transcriptomics Identified Fatty Acid-Binding Proteins Controlling Endothelial Glycolytic and...

Area of Science:

• Cardiovascular Research
• Pulmonary Hypertension Pathogenesis
• Endothelial Cell Biology

Background:

• Pulmonary arterial hypertension (PAH) involves vascular remodeling, leading to right heart failure.
• Endothelial cell expression of fatty acid-binding proteins (FABP4/5) is noted, with elevated FABP4 in PAH patients.
• The specific role of endothelial FABP4/5 in PAH pathogenesis is currently unknown.

Purpose of the Study:

• To investigate the role of endothelial FABP4 and FABP5 in the development of pulmonary arterial hypertension.
• To elucidate the cellular and molecular mechanisms underlying FABP4/5-mediated PAH pathogenesis.

Main Methods:

• Examined FABP4/5 expression in pulmonary artery endothelial cells and lung tissues from PAH patients and rat models.
• Analyzed plasma proteomes, performed echocardiography, hemodynamics, histology, and immunostaining in mouse models (CKO and TKO).
• Utilized bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomics to understand molecular mechanisms.

Main Results:

• FABP4/5 were highly induced in endothelial cells of PAH patients and models, correlating with disease severity.
• Genetic deletion of FABP4/5 in mice reduced pulmonary hypertension, attenuated vascular remodeling, and prevented right heart failure.
• FABP4/5 deletion normalized endothelial cell glycolysis and distal arterial programming, reduced oxidative stress and HIF-2α, and inhibited aberrant endothelial cell proliferation.

Conclusions:

• Pulmonary hypertension induces FABP4/5 expression in pulmonary endothelial cells.
• Aberrant FABP4/5 expression promotes endothelial cell glycolysis and distal arterial programming.
• This contributes to vascular remodeling and exacerbates PAH progression.