Abstract Number: OC 77.1
Meeting: ISTH 2021 Congress
Background: The tissue factor (TF) pathway plays a pivotal role in the development of atherothrombosis. Exposure of TF in ruptured plaques has been implicated in acute coronary syndromes, but contributions of coagulation factor (F) VII to atherosclerosis are unknown. In addition to the synthesis by hepatocytes, FVII is expresses cell autonomously by monocytes and macrophages. The TF-FVIIa complex has cell signaling functions beyond its role in coagulation. TF-FVIIa promotes protease activated receptor (PAR) 2 dependent endosomal signaling and PAR2 has been implicated in the progression of atherosclerotic lesions. Cell signaling by the TF pathway is particularly important in the extravascular space and is supported by coagulation factor synthesis in innate immune cells.
Aims: Because FVII is expressed by macrophages involved in the development of atherosclerosis, we studied the development of atherosclerosis in mice lacking FVII expression in monocytes and macrophages.
Methods: We deleted FVII in myeloid cells (F7f/f/LysMcre mice) and in monocytes and macrophages (F7f/f/Cx3cr1cre mice). We transplanted LDLR-/- mice with bone marrow from FVII-deficient and F7f/f littermate control mice and monitored atherogenesis under a Western diet over 20 weeks by high resolution ultrasound imaging of the carotid arteries and quantitative lesion analysis at the end of the experiment.
Results: F7f/f/LysMcre+ and F7f/f/Cx3cr1cre+ transplanted mice gained weight similarly to controls, but F7f/f/Cx3cr1cre+ transplanted mice showed reduced inflammatory plasma biomarker expression. Unlike mice transplanted with control bone marrow developing increased vessel stiffness over the course of Western diet feeding, monocyte/macrophage FVII-deficient bone marrow-transplanted mice had preserved vessel flexibility. Consistently, F7f/f/LysMcre+ and F7f/f/Cx3cr1cre+ transplanted mice had reduced aortic plaque sizes compared to controls with FVII expression in monocytes and macrophages.
Conclusions: These data point to an important role of cell autonomous synthesis of FVII by macrophages in the exacerbation of inflammation in atherosclerosis, possibly involving extravascular signaling through PARs.
To cite this abstract in AMA style:Wolz R, Ruf W. Monocyte-macrophage Synthesis of FVII Contributes to the Development of Atherosclerosis [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/monocyte-macrophage-synthesis-of-fvii-contributes-to-the-development-of-atherosclerosis/. Accessed June 25, 2022.
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