B. W. Tillman1, T. D. Richards1, V. S. Donnenberg2 1University Of Pittsburgh Medical Center,Division Of Vascular/Department Of Surgery,Pittsburgh, PA, USA 2University Of Pittsburgh Medical Center,Department Of Cardiothoracic Surgery,Pittsburgh, PA, USA
Introduction: Restenosis threatens the longevity of over half of all vascular interventions and circulating progenitor cells have been implicated for their role in this pathology. This contrasts to the conventional paradigm of smooth muscle proliferation in restenosis. Our laboratory has previously demonstrated significant reductions in restenosis after depletion of circulating progenitor cells. Vascular injury signals are also believed to represent an important initial step in restenosis. The exact role of vascular injury signals in restenosis, however, has been difficult to examine given overlapping roles in both progenitor mobilization and smooth muscle proliferation. Previous reports have suggested reduced restenosis among mice with knockout of the vascular injury signal, matrix metalloproteinase 9, (MMP9KO). We hypothesized that this finding may be related to impaired progenitor surge. We further postulated that an approach of administering stem cell factor (SCF) may rescue progenitor surge even in the setting of impaired vascular injury signaling.
Methods: Transgenic MMPKO mice underwent wire injury of the femoral artery as part of an IACUC approved study. Blood was examined on post-operative day 1 using flow cytometry for CD34+/c-kit+ progenitor cells and results were compared to non-operative controls. In a separate experiment, MMP9KO mice were treated with SCF for 4 days prior to flow cytometric analysis of blood specimens. Significance of the results was determined using the Student’s t-test.
Results: In contrast to our findings of progenitor surge after arterial wire injury in C57BL6 animals, our results in MMP9KO mice reveal no significant change among progenitors after wire injury compared to non-operative controls (P=0.74). Administration of SCF demonstrated an average 2.3 fold increase among progenitors compared to saline treated controls (P=0.007)
Conclusion: In summary, our findings suggest that the vascular injury signal MMP9 is an essential factor in progenitor surge after vascular injury. Increased progenitors after administration of SCF suggest this cytokine rescues progenitor surge even amidst deficiency of upstream MMP9. This model presents a unique opportunity to examine the effects of progenitor cells on restenosis independent of the impact of vascular injury signals on vascular smooth muscle proliferation. These results further support a model of vascular injury induced progenitor mobilization that ultimately contributes to restenotic pathology.