Fibroblast activation protein regulates lesion burden and the fibro-inflammatory response in Apoe-deficient mice in a sexually dimorphic manner.

Fibroblast activation protein (FAP) has been established as an inducible and mesenchymal cell-specific mediator of disease progression in cancer and fibrosis. Atherosclerosis is a fibro-inflammatory disease, and FAP was previously reported to be up-regulated in human atherosclerotic plaques compared to normal vessel. Here, we investigated the spatial and temporal distribution of Fap expressing cells in a murine model of atherosclerosis and used a genetic approach to determine if and how Fap impacted disease progression. Fap was found to be expressed predominantly on vascular smooth muscle cells in lesions of athero-prone Apoe mice. Global deletion of Fap (Fap) in Apoe mice accelerated atherosclerotic disease progression in both males and females, with the effect observed earlier in males. Sex-specific effects on lesion morphology were observed. Relative levels of extracellular matrix, fibrotic, and inflammatory cell content were comparable in lesions in male mice regardless of Fap status. In contrast, lesions in Fap female mice were characterized by a more-fibrotic composition due to a reduction in inflammation, specifically a reduction in Mox macrophages. Combined, these data suggest that Fap restrains the progression of atherosclerosis and it may contribute to the sexually dimorphic susceptibility to atherosclerosis by regulating the balance between inflammation-an indicator of vulnerability to plaque rupture, and fibrosis-an indicator of plaque stability.