Abstract 605: High Molecular Weight Kininogen Prevents Vascular Smooth Muscle Progenitor Cell Accumulation to Sites of Vascular Injury and Prevents Neointima Formation
Background: We previously described the anti-adhesive properties of endogenous high molecular weight kininogen (HKa) and its peptide domain 5 (D5) during inflammatory cell recruitment. Since bone marrow-derived vascular progenitor cells substantially contribute to the pathogenesis of vasculoproliferative diseases, this study was aimed to evaluate the effect of HKa and D5 on the accumulation of circulating cells, the function of resident cells, and the resulting vascular remodeling in a mouse model of femoral artery injury.
Methods and Results: 6 weeks after lethal irradiation and bone marrow transplantation from GFP-transgenic into C57/BL6 background mice, the left femoral artery was dilated. Local peri-arterial application of HKa or D5 in a thermoresponsive polymer-gel to the injured artery reduced the accumulation of monocytes /macrophages (HKa: 9.8% ± 1.6%; D5: 4.7% ± 1.4% vs. control: 14.4% ± 1.6%) and prevented the accumulation of bone marrow-derived VSMC (GFP+/SMA+) in the neointima (HK: 16.1% ± 4.7%; D5: 6.6% ± 8.8% vs. control: 25.4% ± 3.4%). HKa and D5 also significantly reduced the number of proliferating (PCNA+) VSMC (HKa: 7.5% ± 1.9%; D5: 4.6% ± 1.9% vs. 11.9% ± 1.9%) and significantly increased the number of apoptotic VSMC in the neointima (HKa: 2.5% ± 2%; D5: 4.2% ± 2.2% vs. 1.6% ± 1.3%), resulting in a significant reduction of neointimal thickening 21 days after vascular injury, (neointima/media ratio HKa: 0.981 ± 0.174; D5: 0.549 ± 0.076 vs. 1.54 ± 0.150; n=6; P<0.05).
Conclusion: Our data indicate that HKa and D5 due to their antiadhesive properties decrease the inflammatory response, the accumulation of bone marrow-derived cells and the proliferation of local neointimal VSMC, resulting in reduced neointima formation. Thus, these data add substantially to the understanding of the role of endogenous HKa, and therapeutic application of HKa may represent a novel approach to prevent vascular proliferative disease.