PDGF-BB/EGR1 Axis Drives Fibroblast Activation Protein Expression to Promote Abdominal Aortic Aneurysm.

Abstract

This study investigates the molecular mechanisms of fibroblast activation protein (FAP) in vascular smooth muscle cells (VSMCs) during abdominal aortic aneurysm (AAA) development. Bulk and single-cell RNA sequencing analysis revealed elevated FAP expression in AAA-derived VSMCs. In a porcine pancreatic elastase (PPE)-induced AAA mouse model, pharmacological inhibition of FAP (Ac-Gly-BoroPro) attenuated aneurysm formation and reduced macrophage infiltration. Further analysis showed that PDGF-BB upregulates FAP expression in VSMCs via the transcription factor EGR1, which binds to the FAP promoter to drive transcription. EGR1 inhibition significantly reduced PDGF-BB-induced FAP expression, highlighting its regulatory role. Additionally, clinical ¹⁸F-FAP inhibitor PET/CT imaging in an infectious AAA patient revealed strong FAP expression in the aneurysm wall. These findings underscore the importance of the PDGF-BB/EGR1/FAP axis in AAA pathogenesis and suggest that targeting FAP could offer therapeutic potential for managing AAA progression.