Vascular Remodeling in Mice Lacking the Cytoplasmic Domain of Tissue Factor
- 5 August 2005
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation Research
- Vol. 97 (3), 293-298
- https://doi.org/10.1161/01.res.0000177533.48483.12
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 (TFΔct/Δct) and compared with TF wild-type mice (TFwt/wt). Morphometric analysis revealed a decrease in the intima/media ratio after vascular injury in arteries from TFΔct/Δct compared with TFwt/wt mice (femoral artery injury: 2.4±0.3 TFwt/wt versus 0.6±0.3 TFΔct/Δct, n=9 to 10, P=0.002; carotis ligation: 0.45+0.11 TFwt/wt versus 0.22+0.03 TFΔct/Δct, 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 TFwt/wt mice showed an increased migratory response toward the TF ligand active site-inhibited FVIIa that was abolished in TFΔct/Δct SMC. In contrast, the unstimulated proliferation rate was increased in TFΔct/Δct SMC compared with TFwt/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.Keywords
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