This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 120/9/774    most recent CIRCULATIONAHA.109.849539v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by Seehaus, S. Articles by Isermann, B. PubMed PubMed Citation Articles by Seehaus, S. Articles by Isermann, B. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB NITRIC OXIDE Related Collections Animal models of human disease Pathophysiology Genetically altered mice Coagulation Thrombin Mechanism of atherosclerosis/growth factors Related Articles

(Circulation. 2009;120:774-784.)
© 2009 American Heart Association, Inc.

Vascular Medicine

Hypercoagulability Inhibits Monocyte Transendothelial Migration Through Protease-Activated Receptor-1-, Phospholipase-Cβ-, Phosphoinositide 3-Kinase-, and Nitric Oxide-Dependent Signaling in Monocytes and Promotes Plaque Stability

Stefanie Seehaus, PhD^*; Khurrum Shahzad, MSc^*; Muhammed Kashif, MSc; Ilya A. Vinnikov, MD; Martin Schiller, MD; Hongjie Wang, MD; Thati Madhusudhan, PhD; Volker Eckstein, PhD; Angelika Bierhaus, PhD; Florian Bea, MD; Erwin Blessing, MD; Hartmut Weiler, PhD; David Frommhold, MD; Peter P. Nawroth, MD; Berend Isermann, MD

From the Department of Medicine I and Clinical Chemistry (S.S., K.S., M.K., I.A.V., H.W., T.M., A.B., P.P.N., B.I.), Department of Medicine V, Hematology/Rheumatology (M.S., V.E.), Department of Medicine III, Cardiology (F.B., E.B.), and Department of Neonatology, Children’s Hospital (D.F.), University of Heidelberg, Heidelberg, Germany; Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.W.); and Blood Research Institute, Blood Center of Wisconsin, Milwaukee (H.W.). Dr Seehaus is currently at the Institute for Animal Developmental and Molecular Biology, Heinrich-Heine University, Düsseldorf, Germany.

Correspondence to Berend Isermann, MD, Department of Medicine I and Clinical Chemistry, University of Heidelberg, INF 410, 69120 Heidelberg, Germany. E-mail berend.isermann{at}med.uni-heidelberg.de

Received January 8, 2009; accepted June 29, 2009.

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/ProApoE^–/– and FVL^Q/QApoE^–/– 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-Cβ, 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-Cβ, 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.

---

 

CLINICAL PERSPECTIVE

Related Articles:

Clinical Summaries
Circulation 2009 120: 717. [Extract] [Full Text]

Countervailing Effects on Atherogenesis and Plaque Stability: A Paradoxical Benefit of Hypercoagulability?

Jeff W. Stevens and Steven R. Lentz
Circulation 2009 120: 722-724. [Extract] [Full Text]

This article has been cited by other articles:

				J. W. Stevens and S. R. Lentz Countervailing Effects on Atherogenesis and Plaque Stability: A Paradoxical Benefit of Hypercoagulability? Circulation, September 1, 2009; 120(9): 722 - 724. [Full Text] [PDF]