Abstract 283: p27kip1 Dose Affects Collateralization Through Arterial Wall Cells
Objectives: p27 deficiency (p27-/-) improves blood flow after hindlimb ischemia through enlargement of a bridge collateral pathway. p27-/- VSMC both migrate and proliferate more than wt VSMC. We hypothesized that p27’s effect on ischemic collateralization is from arterial wall cells and not from bone marrow derived cells.
Methods: p27-/- and wt (C57BL/6) after reciprocal bone marrow transplantation (BMT) and p27+/- female mice underwent left femoral artery ligation. Footpad laser Doppler perfusion imaging was performed weekly. MicroCT scans were performed on both hindlimbs after sacrifice (days 14 and 28 for BMT and p27+/- mice respectively). VSMC were isolated from all groups and used in cell proliferation, migration, and gel contraction assays.
Results: p27-/- mice transplanted with wt bone marrow recovered significantly more blood flow and enlarged bridge collaterals than wt mice transplanted with p27-/- bone marrow (117±15 vs. 55±7 μm, p<0.001). p27+/- mice had intermediate blood flow recovery and had intermediate bridge collateral size (wt 82 ± 22, p27+/- 122±15, and p27-/- 158±18 μm, p< 0.05, Figure 1). In vitro studies showed that p27+/- VSMC proliferated more but did not migrate more than wt VSMC.
Conclusions: p27 deficiency enhances ischemic collateralization via effects on local arterial wall cells rather than on bone marrow derived cells. This may be secondary to increased VSMC proliferation.
Figure 1. MicroCT scans of the ischemic hindlimb of p27-/-, p27+/- and wt mice showing enlargement of bridge collaterals in p27-/- more than p27+/- mice, and absence of this pathway in wt mice. Digital pseudocoloring has been added (magenta-femoral, saphenous, popliteal arteries, blue-collateral arteries, red-unnamed muscular arteries). L-ligation site, 1-bridge collaterals, 2-gracilis collaterals.
Author Disclosures: G.A. Eliahoo: None. O. Bates: None. T.C. Cox: None. G.L. Tang: None.
This research has received full or partial funding support from the American Heart Association.
- © 2015 by American Heart Association, Inc.