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.
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.
Seehaus
Stefanie
S
Department of Medicine I and Clinical Chemistry, University of Heidelberg, INF 410, 69120 Heidelberg, Germany.
Shahzad
Khurrum
K
Kashif
Muhammed
M
Vinnikov
Ilya A
IA
Schiller
Martin
M
Wang
Hongjie
H
Madhusudhan
Thati
T
Eckstein
Volker
V
Bierhaus
Angelika
A
Bea
Florian
F
Blessing
Erwin
E
Weiler
Hartmut
H
Frommhold
David
D
Nawroth
Peter P
PP
Isermann
Berend
B
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
D001057:Apolipoproteins E; D044463:Receptor, PAR-1; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; D054799:Phospholipase C beta; C518034:Plcb1 protein, mouse; D013917:Thrombin