B-Myb Represses Vascular Smooth Muscle Cell Collagen Gene Expression and Inhibits Neointima Formation After Arterial Injury

Abstract

Objectives-The function of B-Myb, a negative regulator of vascular smooth muscle cell (SMC) matrix gene transcription, was analyzed in the vasculature. Methods and Results-Mice were generated in which the human B-myb gene was driven by the basal cytomegalovirus promoter, and 3 founders were identified. Mice appeared to develop normally, and human B-myb was expressed in the aortas. Total B-Myb levels were elevated in aortas of adult transgenic versus wild-type (WT) animals and varied inversely with ␣1(I) collagen mRNA expression. However, neonatal WT and transgenic aortas displayed comparable levels of ␣1(I) collagen mRNA, likely resulting from elevated levels of cyclin A, which ablated repression by B-Myb. Aortic SMCs from adult transgenic animals displayed decreased ␣1(I) collagen mRNA levels. To examine the role of B-Myb after vascular injury, animals were subjected to femoral artery denudation, which induces SMC-rich lesion formation. A dramatic reduction in neointima formation and lumenal narrowing was observed in arteries of B-myb transgenic versus WT mice 4 weeks after injury. Key Words: Myb Ⅲ collagen Ⅲ cyclin A Ⅲ aorta Ⅲ femoral artery S mooth muscle cells (SMCs), the major cellular constituents of the medial layer of an artery, are responsible for synthesis and deposition of connective tissue proteins (including types I and V collagen, elastin, and proteoglycans) during artery development. 1 After the artery is formed, SMCs differentiate into a contractile phenotype. 1 During atherosclerosis development, a response to vascular injury is elicited. After monocyte invasion, SMCs migrate to the intima and dedifferentiate to a synthetic phenotype, displaying modest rounds of proliferation followed by matrix synthesis. 2,3 Deposition of matrix proteins, lipids, and minerals results in atherosclerotic plaque formation. Rupture of the fibrous cap of plaque with resultant exposure of thrombogenic subendothelial plaque constituents is the critical event that leads to thromboembolic complications in atherosclerotic coronary and carotid artery disease. [2][3][4] Atherosclerotic lesions are frequently treated by balloon angioplasty and stent placement. However, reoccurrence of arterial narrowing at the site of balloon angioplasty, termed restenosis, occurs in 30% to 50% of patients. 1 Acute disruption of the protective endothelial lining at the site of angioplasty appears to trigger excessive SMC hyperplastic responses, 5 extracellular matrix deposition, 3 and local vessel remodeling. 6,7 Cultured vascular SMCs from adult animals exhibit predominantly a synthetic phenotype, expressing genes encoding types I, III, and V/XI collagen at confluence or when deprived of serum growth factors, 8 -10 whereas during exponential growth, only low levels of matrix proteins are produced. Furthermore, basic fibroblast growth factor (bFGF), a potent inducer of SMC proliferation, decreased ␣1(I) and ␣2(V) collagen gene expression at the transcriptional level in bovine SMCs. 11 Overall, an inverse relationship exists between the p...

Generation of a conditional allele of the B‐myb gene

“…Hence, mutants of Dm-Myb have various mitotic defects, including centrosome amplification and genome instability (Fung et al, 2002), which may in part be due to a requirement for Dm-Myb to induce cyclin B expression (Okada et al, 2002). In addition, studies in neuroblastoma and B-cell lines have implicated B-Myb as a differentiation and antiapoptotic factor (Raschella et al, 1995;Lang et al, 2005), while B-Myb has been shown to regulate extracellular matrix molecule gene expression in vascular cells (Hofmann et al, 2004) and adhesion molecule expression in embryonic stem (ES) cells (Iwai et al, 2001).…”

Vascular injury response in mice is dependent on genetic background

“…However, our data clearly demonstrate that the genetic background of mice has a considerable influence on the extent of neointima formation in response to vascular injury. Although much effort has been spent on optimizing technical aspects of injury models and on studying mitogenic or endothelial factors (3,8,11,16), it may even be hypothesized that an optimal genetic background of mice may be necessary to unravel a significant influence of a certain factor. In our studies, we used mice of a mixed background that were backcrossed into either the 129 strain or the DBA strain.…”

Common signatures for gene expression in postnatal patients with patent arterial ducts and stented arteries

“…Experimental approaches aimed at understanding the molecular details of neointimal formation by analysis of gene expression could contribute to the development of treatments with reduced side effects. [11][12][13][14][15] So far, the best characterized animal model for study of the arterial duct is the sheep. The genomic sequence of the sheep, however, is not yet completed.…”