Thrombomodulin plays an important role in arterial remodeling and neointima formation in mouse carotid ligation model.
Thrombomodulin (TM) is a cell membrane-bound glycoprotein that functions as a thrombin cofactor in the activation of protein C. Its protein structure includes a N-terminal lectin-like domain (D1), 6 epidermal growth factor repeats (D2), a serine-threonine-rich region (D3), a transmembrane domain (D4) and a short cytoplasmic tail (D5). Recent studies have demonstrated the direct effect of TM on cellular proliferation, adhesion and inflammation. In the study, we investigated the role of TM in vascular remodeling and neointima formation in a mouse carotid ligation model. TM expressions on the endothelium, neointima and media were examined in the ligated carotid artery by immunohistochemistry and quantitative real-time reverse transcription PCR. Endothelial TM expression decreased after ligation and appeared later in the media and neointima, which is quite similar to the appearance of TM in the human atherosclerotic process. Recombinant TMD123 was prepared. It was effective for thrombin-dependent protein C activation and the inhibition of leukocyte adhesion to the vessel wall after carotid ligation. Recombinant TMD123 and saline was administered immediately before and after carotid ligation. The TM-treated arteries demonstrated significantly less arterial dilatation (30279 +/- 12605 vs 73789 +/- 15073 microm(2), p < 0.05) in response to less neointima formation (14179 +/- 6538 vs 42227 +/- 8754 microm(2), p < 0.05) at 4 weeks after ligation. Our data indicated that there was a compensatory increase in TM expression in the media and neointima in relation to the reduced endothelial TM after carotid ligation. Early recombinant TM treatment in mice undergoing carotid ligation altered vascular remodeling and decreased the severity of neointima formation.
Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
Yi-Heng
YH
Li
Shu-Lin
SL
Liu
Guey-Yueh
GY
Shi
Guan-Hsiung
GH
Tseng
Ping-Yen
PY
Liu
Hua-Lin
HL
Wu
D000818:Animals; D002340:Carotid Artery Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D017536:Carotid Artery, Common / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D008026:Ligation; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012044:Regression Analysis; D018180:Thrombomodulin / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017540:Tunica Media / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
D012333:RNA, Messenger; D011994:Recombinant Proteins; D018180:Thrombomodulin