Abstract 17597: Deletion of Fibroblast Activation Protein (FAP) Attenuates Atherosclerotic Lesion Development via Changes in the Accumulation of Fibrillar Collagen and in Inflammatory Cell Recruitment
Atherosclerosis and the formation of vascular lesions is a highly integrated process involving the endothelium, vascular smooth muscle cells (VSMCs), inflammatory cell recruitment and lipid metabolism. The crosstalk between these cells and pathways impacts the size, composition and architecture of the lesion and consequently clinical outcome. The formation of a VSMC- and matrix-rich fibrotic lesion, characterized by high collagen content, is thought to favor lesion stability, however matrix accumulation in vessels increases their elastic modulus (stiffness), a condition that favors atherogenesis. FAP is a membrane serine protease involved in collagen metabolism that is upregulated in tissues undergoing tissue remodeling. FAP was recently shown to be expressed in human atherosclerotic lesions, yet its role in this setting is not understood. The aim of this study was to therefore determine if FAP plays an important role in lesion development. We found that in vitro, FAP was upregulated in activated primary VSMCs, and correlated with an increase in αSMA and type-I collagen expression. In a mouse model of atherosclerosis (apoE-knockout mice), global deletion of FAP inhibited lesion development. Lesion architecture in the absence of FAP was associated with increased fibrillar collagen and matrix accumulation, coupled with a decrease in inflammatory cell content. Furthermore, macrophage homing to atherosclerotic lesions was attenuated in the absence of FAP. Interestingly, vascular stiffness was increased under homeostatic conditions in FAP-knockout mice. Based on these data, it appears that FAP plays an active role in atherosclerotic lesion development by regulating VSMC function. Targeted inhibition of FAP may decrease overall lesion burden, inhibit inflammatory cell homing and increase lesion stability through its ability to alter lesion architecture by favoring matrix-rich lesions over inflammation.
- © 2013 by American Heart Association, Inc.