Atorvastatin inhibits plaque development and adventitial neovascularization in ApoE deficient mice independent of plasma cholesterol levels.
Excessive adventitial neovascularization is one of the hallmarks of atherosclerotic plaque progression and is associated with an increased plaque burden by facilitating leukocyte influx and perivascular inflammation. Statins act atheroprotective by reducing plasma cholesterol levels and by quenching inflammation, but recent studies suggest that they may also affect neovascularization. In this study, we aimed to investigate this notion in apoE(-/-) mice. Advanced carotid artery lesions were induced by perivascular collar placement in mice on western type diet or diet supplemented with atorvastatin (0.003%, w/w). Atorvastatin treatment did not affect diet induced body weight gain and did not lower plasma total cholesterol levels. Plaque size at 8 weeks after collar placement was significantly reduced in atorvastatin treated mice compared to control mice, while also necrotic core size was significantly lower in atorvastatin treated mice. Interestingly, atorvastatin treatment reduced the number of perivascular CD31(+) neovessels by almost 40%. Furthermore, endothelial proliferation was significantly inhibited by atorvastatin treatment in vitro. In conclusion, atorvastatin treatment inhibits plaque development in ApoE deficient mice independent of plasma total cholesterol levels. Given the profound inhibition of adventitial neovascularization, we propose that statins may partly exert their protective effects by modulating this process, identifying yet another atheroprotective mechanism for statins.
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands. i.bot@lacdr.leidenuniv.nl
Ilze
I
Bot
J Wouter
JW
Jukema
Inge M
IM
Lankhuizen
Theo J C
TJ
van Berkel
Erik A L
EA
Biessen
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D000069059:Atorvastatin; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000097:blood*; D003238:Connective Tissue / Q000098:blood supply*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D055806:Microvessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D013997:Time Factors
D020533:Angiogenesis Inhibitors; D001057:Apolipoproteins E; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011758:Pyrroles; D002784:Cholesterol; D000069059:Atorvastatin