Vascular remodeling in mice lacking the cytoplasmic domain of tissue factor.
Tissue factor (TF), the cell surface receptor for the serine protease FVIIa supports cell migration by interaction with the cytoskeleton. Intracellular signaling pathways dependent on the cytoplasmic domain of TF modify cell migration and may alter vascular remodeling. Vascular remodeling was analyzed in a femoral artery injury and a blood flow cessation model in mice with a targeted deletion of the 18 carboxy-terminal intracellular amino acids of TF (TF(Deltact/Deltact)) and compared with TF wild-type mice (TF(wt/wt)). Morphometric analysis revealed a decrease in the intima/media ratio after vascular injury in arteries from TF(Deltact/Deltact) compared with TF(wt/wt) mice (femoral artery injury: 2.4+/-0.3 TF(wt/wt) versus 0.6+/-0.3 TF(Deltact/Deltact), n=9 to 10, P=0.002; carotis ligation: 0.45+0.11 TF(wt/wt) versus 0.22+0.03 TF(Deltact/Deltact), n=12 to 14, P=0.09). This was caused by an increase in the media by 54% (P=0.04) in the femoral artery model and by 32% (P=0.03) after carotis ligation and was associated with an increased number of proliferating cells. Isolated aortic smooth muscle cells (SMCs) of TF(wt/wt) mice showed an increased migratory response toward the TF ligand active site-inhibited FVIIa that was abolished in TF(Deltact/Deltact) SMC. In contrast, the unstimulated proliferation rate was increased in TF(Deltact/Deltact) SMC compared with TF(wt/wt) SMCs. Thus, retention of SMCs attributable to a migratory defect and increased proliferation results in thickening of the media and in decrease in neointima formation after arterial injury. TF cytoplasmic domain signaling alters vascular remodeling and, thereby, may play a role in the development of restenosis, atherosclerotic disease, and neovascularization.
Ott
Ilka
I
Deutsches Herzzentrum und 1, Medizinische Klinik der Technischen, Universität München, Germany. ott@dhm.mhn.de
Michaelis
Cornelia
C
Schuermann
Maren
M
Steppich
Birgit
B
Seitz
Isabell
I
Dewerchin
Mieke
M
Zohlnhofer
Dietlind
D
Wessely
Rainer
R
Rudelius
Martina
M
Schömig
Albert
A
Carmeliet
Peter
P
D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003593:Cytoplasm / Q000737:chemistry*; D005263:Femoral Artery / Q000473:pathology; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D013925:Thromboplastin / Q000737:chemistry / Q000502:physiology*; D017539:Tunica Intima / Q000473:pathology*; D017540:Tunica Media / Q000473:pathology*
D013925:Thromboplastin