Abstract 18612: Normal c-Myb Activity is Critical for Both Vessel-Resident and Bone Marrow-Derived Cell Responses to Arterial Remodeling Following Injury

Abstract

Background: The c-myb proto-oncogene regulates the proliferation of adult vascular smooth muscle cells (VSMCs) and the differentiation of VSMCs from a specific embryonic stem cell-derived hematogenic progenitor cell population. It remains unknown if c-myb has a critical role in the proliferation or potential (trans)differentiation of bone marrow (BM)-derived vs. vessel resident cells in intimal hyperplasia following wire denudation carotid artery injury (CI). We used a mouse harboring a non-lethal point mutation in c-myb resulting in a hypomorphic (h) allele of c-myb with defective c-Myb activity. Previously, we showed that hypomorphic (h/h) mice on a C57BL6 background have decreased neointimal hyperplasia versus wild-type (wt) mice following CI. While BM transplantation (BMT) of h/h BM into wt recipients (h/h→wt) inhibited neointimal hyperplasia compared to injured wt→h/h mice, the role of c-myb in vessel resident cells remained unclear. Also, as many strain-specific differences exist in BM-derived cells, h/h mice were backcrossed 10 generations into a FVB/N background to study injury response. Methods and results: Reciprocal BMTs were performed in 5 wk old mice, which were allowed to reconstitute for 7 wks before CI. Injured arteries from wt→wt mice had greater intima formation than h/h→wt mice (19,222±2,622 vs. 8,080±1337 μm2; p<0.0001; N= 7/group), with no differences observed in uninjured BMT controls. However, reconstitution of h/h mice with WT BM had no effect on neointimal proliferation compared to h/h→h/h mice (14,519±486 vs. 13,437±1,175 μm2; p=NS; N= 7/group). To examine cell integration and (trans)differentiation of BM-derived cells, we generated h/h and wt mice with eGFP expression. When subjected to CI, eGFPxh/h mice show decreased neointimal hyperplasia consistent with non-eGFPxh/h mice. Wire injured 10-12wk old FVB/N h/h mice had reduced intima area (30,251±2,306 μm2 vs. 57,059±9,336 μm2; p=0.11) and I/M ratio (0.53±.010 vs 1.19±0.12; p=0.049) versus FVB/N wt mice (N=3/group). Conclusions: Effects of defective c-myb activity do not appear to be strain specific. Our data suggest that c-myb has a critical role in regulating neointimal hyperplasia in both vessel resident and BM-derived cell populations.