title: Vascular remodeling in mice lacking the cytoplasmic domain of tissue factor.
abstract: 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.
authors: Deutsches Herzzentrum und 1, Medizinische Klinik der Technischen, Universität München, Germany. ott@dhm.mhn.de
authors: Ilka
authors: I
authors: Ott
authors: Cornelia
authors: C
authors: Michaelis
authors: Maren
authors: M
authors: Schuermann
authors: Birgit
authors: B
authors: Steppich
authors: Isabell
authors: I
authors: Seitz
authors: Mieke
authors: M
authors: Dewerchin
authors: Dietlind
authors: D
authors: Zohlnhofer
authors: Rainer
authors: R
authors: Wessely
authors: Martina
authors: M
authors: Rudelius
authors: Albert
authors: A
authors: Schömig
authors: Peter
authors: P
authors: Carmeliet
mesh_terms: 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*
chemical_list: D013925:Thromboplastin