title: Hypercoagulability inhibits monocyte transendothelial migration through protease-activated receptor-1-, phospholipase-Cbeta-, phosphoinositide 3-kinase-, and nitric oxide-dependent signaling in monocytes and promotes plaque stability.
abstract: 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.
  
  
  RESULTS
  De novo atherogenesis was evaluated in 2 mouse models with hyperlipidemia and genetically imposed hypercoagulability (TM(Pro/Pro)ApoE(-/-) and FVL(Q/Q)ApoE(-/-) 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-Cbeta, 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-Cbeta, 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.
authors.affiliation: Department of Medicine I and Clinical Chemistry, University of Heidelberg, INF 410, 69120 Heidelberg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Seehaus
authors.forename: Khurrum
authors.initials: K
authors.lastname: Shahzad
authors.forename: Muhammed
authors.initials: M
authors.lastname: Kashif
authors.forename: Ilya A
authors.initials: IA
authors.lastname: Vinnikov
authors.forename: Martin
authors.initials: M
authors.lastname: Schiller
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.forename: Thati
authors.initials: T
authors.lastname: Madhusudhan
authors.forename: Volker
authors.initials: V
authors.lastname: Eckstein
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Florian
authors.initials: F
authors.lastname: Bea
authors.forename: Erwin
authors.initials: E
authors.lastname: Blessing
authors.forename: Hartmut
authors.initials: H
authors.lastname: Weiler
authors.forename: David
authors.initials: D
authors.lastname: Frommhold
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism; D005260:Female; D006949:Hyperlipidemias / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D054799:Phospholipase C beta / Q000378:metabolism*; D044463:Receptor, PAR-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013917:Thrombin / Q000378:metabolism; D019851:Thrombophilia / Q000276:immunology / Q000378:metabolism*; D014657:Vasculitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D044463:Receptor, PAR-1; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; D054799:Phospholipase C beta; C518034:Plcb1 protein, mouse; D013917:Thrombin