Background-Clinical studies failed to provide clear evidence for a proatherogenic role of hypercoagulability. This is in contrast to the well-established detrimental role of hypercoagulability and thrombin during acute atherosclerotic complications. These seemingly opposing data suggest that hypercoagulability might exert both proatherogenic and antiatherogenic effects. We therefore investigated whether hypercoagulability mediates a beneficial effect during de novo atherogenesis. Methods and Results-De novo atherogenesis was evaluated in 2 mouse models with hyperlipidemia and genetically imposed hypercoagulability (TM Pro/Pro ApoE Ϫ/Ϫ and FVL Q/Q ApoE Ϫ/Ϫ mice). In both mouse models, hypercoagulability resulted in larger plaques, but vascular stenosis was not enhanced secondary to positive vascular remodeling. Importantly, plaque stability was increased in hypercoagulable mice with less necrotic cores, more extracellular matrix, more smooth muscle cells, and fewer macrophages. Long-term anticoagulation reversed these changes. The reduced frequency of intraplaque macrophages in hypercoagulable mice is explained by an inhibitory role of thrombin and protease-activated receptor-1 on monocyte transendothelial migration in vitro. This is dependent on phospholipase-C␤, phosphoinositide 3-kinase, and nitric oxide signaling in monocytes but not in endothelial cells. Conclusions-Here, we show a new function of the coagulation system, averting stenosis and plaque destabilization during de novo atherogenesis. The in vivo and in vitro data establish that thrombin-induced signaling via protease-activated receptor-1, phospholipase-C␤, phosphoinositide 3-kinase, and nitric oxide in monocytes impairs monocyte transendothelial migration. This likely accounts for the reduced macrophage accumulation in plaques of hypercoagulable mice. Thus, in contrast to their role in unstable plaques or after vascular injury, hypercoagulability and thrombin convey a protective effect during de novo atherogenesis. (Circulation. 2009;120:774-784.)Key Words: atherosclerosis Ⅲ blood coagulation Ⅲ endothelium Ⅲ plaque Ⅲ monocytes A therosclerosis is a slowly progressive disease characterized by vascular remodeling and intraplaque accumulation of monocyte-derived macrophages. The role of thrombin and the protease-activated receptor-1 (PAR-1) in atherosclerosis is generally perceived as being detrimental on the basis of their pathogenic role in acute atherosclerotic complications or after vascular injury. [1][2][3] This perception is fostered by a study evaluating de novo atherogenesis in experimental murine atherosclerosis, which showed larger plaques in hypercoagulable factor V Leiden mice (FVL Q/Q ). 4 However, several large studies evaluating the role of genetic risk factors of hypercoagulability (eg, factor V Leiden [FV G1691A] or prothrombin variant [FII G20210A]) failed to show an association between hypercoagulability and the prevalence of Received January 8, 2009; accepted June 29, 2009. From the Department of Medicine I and Clinical Chemistr...

Information regarding the distribution and persistence of DNA encapsulated in poly-(lactide co-glycolide) microspheres was collected to provide additional information regarding the safety of DNA vaccines and to support the clinical testing of this new delivery system for DNA. Plasmid DNA was encapsulated in poly(lactide co-glycolide) microspheres and the distribution and persistence of plasmid in murine tissues resulting from parenteral administration were examined by a sensitive PCR assay. Encapsulated DNA delivered by intramuscular or subcutaneous injection can be detected for 100 days post-injection and is distributed primarily at the site of injection and the lymphoid organs. Intravenous administration results in more widespread dissemination with long term persistence limited to the lymphoid organs and those of the reticuloendothelial system. Specific cellular uptake of DNA by professional antigen presenting cells (APCs) following injection suggests the utility of microspheres as DNA delivery agents. Distribution and persistence studies support the safety of encapsulated DNA and the specific cellular uptake of DNA by professional APCs following injection suggests the utility of microspheres as DNA delivery agents.

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