Abstract 14294: Normal c-Myb Activity is Required for Bone Marrow-Derived Cells to Contribute to Arterial Remodeling Following Injury
Background: We showed that the c-Myb transcription factor regulates proliferation and differentiation of contractile vascular smooth muscle cells (VSMC) in adult mice and embryoid bodies respectively, the latter mediated by control over a specific hematopoietic and angiogenic progenitor. However, the definitive role of c-Myb in the proliferation and potential (trans)differentiation of bone marrow (BM)-derived vs. vessel resident cells in arterial remodeling following injury in the adult has eluded genetic examination due to the embryonic lethality of c-myb-/- mice from hematopoietic failure. To overcome this, we obtained a mouse with an ENU-generated point mutation in c-myb, resulting in a hypomorphic c-myb (h) allele with non-lethal loss of c-Myb activity.
Methods & Results: Histology of common carotid arteries of 12 wk-old male c-mybh/h and c-mybwt mice was performed 14 days after wire denudation injury (CI). Uninjured vessels from wt and h/h mice did not differ in lumen, intima (I), and media (M) morphometry or I/M ratio. Following CI, h/h mice showed reduced intima formation (15,068±3,347 vs. 43,059±12,628 μ m2; p<0.0001; N=5/group) and I/M ratio (0.27±0.04 vs. 0.68 ±0.16; p<0.0001) than wt controls. Both wt and h/h vessels manifest increased outer elastic lamina circumference post-CI, but only h/h vessels had increased lumen circumference vs. uninjured controls (1,493±60 vs. 1,165±29 μ m; p<0.05). qRT-PCR showed that several extracellular matrix (ECM) genes failed to increase expression in h/h arteries following CI, which may underlie their dilation. To explore the relative contribution of BM vs. vessel processes, reciprocal BM transplants were performed in 5 wk old mice, which were allowed to reconstitute their BM for 7 wks before CI. Injured arteries from wt→h/h mice had greater intima formation than h/h→wt mice (11,137±3,142 vs. 4,539±327 μ m2; p<0.05; N= 3/group), with no differences observed in uninjured BM- transplanted controls.
Conclusion: The blunted arterial remodeling response observed in h/h mice is due to a c-Myb-dependent defect in BM-derived cell populations. Our data suggest further that c-Myb plays a role in the elaboration of ECM-related genes following arterial injury.
- © 2012 by American Heart Association, Inc.