Abstract 187: Prevention of Circulating Progenitor Surge After Vascular Injury Effectively Reduces Restenosis
Background: Restenosis is an aberrant healing response that leads to failure of half of all vascular interventions and circulating progenitor cells have been implicated in restenotic pathology. Based on our previous findings of a surge specific to macrovascular injury, we hypothesized that a surge among progenitors and vascular injury signaling would be evident in the murine model and that an approach to prevent this surge would reduce restenosis.
Methods: C57BL6 mice underwent injury of the femoral artery following either a depleting antibody to the progenitor marker sca-1 or a control antibody (n=8 per group). A third group had a non-vascular surgery (n=5). Antibody was administered pre-op and then until day 9. Blood and bone marrow were collected on days 1, 3, and 9 and analyzed by flow cytometry for progenitor markers CD34 and c-kit. Plasma was analyzed for the vascular injury signal, stromal cell-derived factor 1/CXCL12 (sdf1alpha). Vessel explants were imaged with lectin microscopy. Finally, animals treated with either sca-1 depleting antibody (n=4) or an isotype control (n=3) underwent vessel explant at 28 days and a lumen ratio was calculated.
Results: Microscopy confirmed injury of endothelial monolayer and serologically, wire injury increased sdf1alpha by over 3 fold. Injury of the femoral artery resulted in a surge of CD34+/c-kit+ progenitors by over 2.2 fold relative to non-operative controls with a peak on day 1. Furthermore, this surge was prevented by treatment with a sca-1 antibody (P= 0.004). At 28 days, progenitor depletion increased the lumen from 20% among isotype treated controls to 79% among animals treated with direct progenitor depletion (P=0.04).
Conclusions: It has not been previously demonstrated whether changes among progenitor cells impact restenotic pathology. Our findings suggest that a surge occurs in both a key vascular injury cytokine and among circulating progenitor cells after macrovascular injury. We have further demonstrated the efficacy of a depleting sca-1 antibody to mitigate progenitor surge and most importantly to reduce restenosis in a significant fashion. Future studies of strategies to block circulating progenitor cells may provide new therapies for this prevalent life and limb threatening disease.
Author Disclosures: B.W. Tillman: None. J. Kelly: None. T.D. Richards: None. A.F. Chen: None. A.D. Donnenberg: None. V. Donnenberg: None.
- © 2014 by American Heart Association, Inc.