Regulation of smooth muscle cell migration and integrin expression by the Gax transcription factor

Homeobox transcription factors specify body plan by regulating differentiat ion, proliferation, and migration at a cellular level. The homeobox transcr iption factor Gax is expressed in quiescent vascular smooth muscle cells (V SMCs), and its expression is downregulated by vascular injury or other cond itions that lead to VSMC proliferation. Previous investigations demonstrate that Gax may regulate VSMC proliferation by upregulating the cyclin-depend ent kinase (cdk) inhibitor p21. Here we examined whether Gax influences VSM C migration, a key feature in the development of stenotic lesions after bal loon injury. Transduction of a Gax cDNA inhibited the migratory response of VSMCs toward PDGF-BB, basic fibroblast growth factor, or hepatocyte growth factor/scatter factor. Gax expression also inhibited migration of NIH.3T3 fibroblasts and embryonic fibroblasts lacking p53. Gax was unable to inhibi t the migration of fibroblasts lacking p21, but this effect could be restor ed in these cells by providing exogenous p21 or by overexpressing another c dk inhibitor, p16. Flow cytometric analysis implicated a Gax-mediated downr egulation of alpha(v)beta(3) and alpha(v)beta(5) integrin expression in VSM Cs as a potential cause for reduced cell motility. Gax specifically downreg ulated pg and ps in VSMCs in culture and after acute vascular injury in viv o. Repression of integrin expression was also found in NIH 3T3 cells and p5 3 knockout fibroblasts, but not in p21-knockout fibroblasts, unless these c ells express exogenous p21 or p16. These data suggest that cycle progressio n, integrin expression, and cell migration can be regulated in VSMCs by the homeobox gene product Gax.