Characterization of simple and reproducible vascular stenosis model in hypercholesterolemic hamsters.
The importance of low-density lipoprotein (LDL) in the etiology of atherosclerosis is well recognized. We have established a reproducible stenosis model in hypercholesterolemic hamsters, and the process of arterial stenosis by thrombus or neointima was studied and compared with that in normal hamsters. The level of plasma LDL was 4.6 times higher in hamsters fed a high-cholesterol diet than in hamsters fed normal food. Endothelial injury in right common carotid arteries was induced using a modified catheter. Arterial blood flow was monitored continuously using a Doppler flow probe. Arterial patency after the initiation of injury in high-cholesterol hamsters was significantly changed as compared with that of normal hamsters. Neointima was observed 2 wk after the vascular injury. The neointimal area of high-cholesterol hamsters was significantly larger than that of normal hamsters. To characterize the stenosis in hypercholesterolemic hamsters, we measured platelet aggregation, thrombin time, activated partial thromboplastin time, and proliferating smooth muscle cells (SMC) in vitro and in vivo. The half-maximal inhibitory concentration value for platelet aggregation induced by thrombin or collagen, the DNA synthesis stimulated by platelet-derived growth factor (PDGF)-BB, and 5-bromo-2-deoxy-uridine labeling indices (proliferating index of SMC in vivo) in high-cholesterol hamsters were each significantly higher than the comparable value from normal hamsters. However, specific binding of PDGF-BB in SMC was not different between the two types of hamsters. Furthermore, we investigated the inhibitory effects of probucol or losartan on neointima formation using this model. Probucol, but not losartan, significantly reduced the neointimal area in hypercholesterolemic hamsters. These findings indicated that high levels of plasma LDL strongly contributed to the development of thrombus and neointima formation via both up-regulation of platelet aggregation and the enhancement of SMC proliferation. This stenosis model may be useful for the investigation of hypercholesterolemia-associated cardiovascular diseases.
Matsuno
H
H
Department of Pharmacology, Gifu University School of Medicine, Japan. leuven@cc.gifu-u.ac.jp
Kozawa
O
O
Niwa
M
M
Abe
A
A
Takiguchi
Y
Y
Uematsu
T
T
D000818:Animals; D000077214:Becaplermin; D001783:Blood Flow Velocity; D002339:Carotid Arteries / Q000473:pathology / Q000648:ultrastructure; D002341:Carotid Artery Thrombosis / Q000097:blood / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000494:pharmacology; D003251:Constriction, Pathologic / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D006937:Hypercholesterolemia / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008647:Mesocricetus; D008854:Microscopy, Electron; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D010974:Platelet Aggregation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology; D011341:Probucol / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D015203:Reproducibility of Results; D017539:Tunica Intima / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure; D014652:Vascular Diseases / Q000097:blood / Q000378:metabolism* / Q000473:pathology
D002791:Cholesterol, Dietary; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D004247:DNA; D002784:Cholesterol; D019808:Losartan; D011341:Probucol