Bone marrow derived cells with defective c-Myb activity protect against neointimal remodeling following injury

Abstract

Purpose: We previously showed that the transcription factor c-myb regulates the differentiation of contractile vascular smooth muscle cells in embryonic stem cell-derived embryoid bodies. While we also showed that c-Myb regulates the expansion of a specific embryonic hemangiogenic progenitor, it is unclear if this population has a role in the adult animal. However, the role of c-Myb in the proliferation and potential (trans)differentiation of bone marrow (BM)-derived vs. vessel-resident cells in arterial remodelling in the adult has eluded genetic examination due to the embryonic lethality of c-myb-/- mice from hematopoietic failure. To examine the role of c-myb in BM-derived vs. vessel-resident cells, we have used a mouse harboring a non-lethal point mutation resulting in a hypomorphic (h) allele of c-myb with defective c-Myb activity. Methods and results: Histology of common carotid arteries of 12 wk-old male c-mybh/h and c-mybwt mice was performed 14 days after carotid artery wire denudation injury. Uninjured vessels from wt and h/h mice did not differ in lumen, intima, and media morphometry or I/M ratio. Following wire injury, h/h mice showed reduced intima formation (16,723±2,550 vs. 31,402±49,890 μm2; p<0.05; N=6-7/group) and I/M ratio (0.313±0.044 vs. 0.565±0.089; p<0.01) than wt controls. To determine the relative contribution of BM-derived vs. vessel cells in arterial remodeling, reciprocal BM transplants were performed in 5wk old wt and h/h mice, which were allowed to reconstitute their BM for 7 wks before wire injury. Compared to wt→wt mice, injured arteries from h/h→wt mice had decreased intima formation (19,222±2,622 vs. 8,080±1,337 μm2; p<0.0001; N= 7/group) and I/M ratio (0.491±0.068 vs. 0.217±0.01; p<0.0001). However, injured arteries from wt→h/h mice had no differences in intima formation as compared to h/h→h/h mice (14,519±486 vs. 13,437±1,175 μm2; p=NS; N= 7/group), with no differences observed in uninjured BM-transplanted control arteries. Conclusions: The blunted arterial remodelling response observed in h/h→wt mice is due to a c-Myb dependent defect in BM-derived cell populations that participate in the pathogenesis of neointimal proliferation following arterial injury.