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.