P369Cleaved high molecular weight kininogen (HKa) prevents neointima formation following vascular injury

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Abstract

Purpose

The cleavage of high molecular weight kininogen (HK) results in therelease of bradykinin and a cleaved form of HK (HKa). We previously could show that HKa and its peptide domain 5 (D5) alone exert anti-adhesive properties during inflammatory cell recruitment via binding to extracellular matrix proteins and integrins, promoting apoptosis in vascular 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 formation.

Methods

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 control to the dilated artery in a thermosensitive pleuronic gel. Vessels were harvested 1 day after injury to document the sustained release of the substances and at 3 weeks after injury for morphometric analysis and immunohistochemistry (n=6).

Results

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 ± 0.150; P < 0.05). The attenuation of the neointimal lesion was accompanied by a reduced accumulation of EGFP + -cells and monocytes/ macrophages in the treatment groups. Confocal microscopy revealed that EGFP + -cells did not co-express smooth muscle myosin heavy chain or calponin, indicating that BM-derived cells did not trans-differentiate into bona fide SMC. Importantly, HKa and 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 re-endothelialization were not different.

Conclusion

These data identify the cleaved form of kininogen (HKa) and especially it's peptide domain 5 as an endogenous inhibitor of the inflammatory response following vascular injury due to its anti-adhesive properties, which also reduces proliferation of local vascular cells. Moreover,the application of HKa or D5 may provide a novel therapeutic strategy for the treatmentof vascular proliferative diseases.

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