Abstract 19858: High Molecular Weight Kininogen Inhibits Neointima Formation following vascular injury
We previously were able to demonstrate that endogenous high molecular weight kininogen (HKa) and its peptide domain 5 (D5) exert anti-adhesive properties during inflammatory cell recruitment and have pro-apoptotic effects on vascular smooth muscle cells. In this study, we investigated the effects of HKa and D5 on the accumulation of circulating cells and the function of resident vascular cells in a mouse model of neointima (NI) formation. C57BL/6 mice were lethally irradiated and rescued with bone marrow from transgenic mice expressing enhanced green fluorescence protein (EGFP). Wire induced injury of the femoral artery was performed on chimeric mice with local application of HKa, D5, or vehicle to the dilated artery in a thermosensitive pleuronic gel. Vessels were harvested at 1 day after injury to test the sustained release of the substances (n=3) and at 3 weeks after injury for morphometric analysis and immunohistochemistry (n=6). NI formation was significantly reduced after treatment with HKa and even more prominent after D5 application (HKa: 0.981 ± 0.174; D5: 0.549 ± 0.076 vs. 1.54 ± 0.15; P<0.05). The attenuation of the NI was accompanied by a reduced accumulation of EGFP+-cells and monocytes/ macrophages in the treatment groups. Even though a substantial fraction of smooth muscle cells is supposed to be derived from circulating progenitor cells, a detailed analysis with confocal microscopy revealed that only very few EGFP+-cells stained positive for α-smooth muscle actin, whereas no BM-derived cells were found to express smooth muscle myosin heavy chain or calponin. Application of HKa or D5 significantly reduced the number of proliferating resident smooth muscle cells in the vascular wall (P<0.05). In contrast, the ratio of apoptotic cells/ all neointimal cells was increased in the treatment groups, although the absolute numbers of apoptotic vascular cells as well as the process of reendothelialization were not different. In conclusion, we show that HKa and D5 decrease the inflammatory response to the vascular injury due to their anti-adhesive properties and thus reduce the proliferation of local vascular cells. Therefore, application of HKa or D5 may provide a novel therapeutic strategy for the prevention of vascular proliferative diseases.
- © 2010 by American Heart Association, Inc.