Vascular smooth muscle cell proliferation: basic investigations and new therapeutic approaches

Our investigations are based upon the hypothesis that synthesis and release of numerous mitogens allow interaction with a correspondingly large set of specific receptors to initiate a variety of secondary messages which eventually lead to SMC proliferation and migration. Unfortunately, the experimental tools available for studying these critical biologic systems under in vivo conditions are quite limited. Previous investigators have partially elucidated the growth factors responsible for intimal accumulation by infusing specific antibodies against individual mitogens such as PDGF or bFGF. However, no general approach was available to identify critical intracellular intermediates of the above pathway. We thought that antisense oligonucleotides might be useful in pinpointing these key components by specifically inhibiting their expression and then determining the effects of the suppression on SMC response in vivo. Data summarized above strongly imply that c-myb is a critical intermediate of a common mitogenic pathway required by all growth factors involved in SMC migration and growth. Given the previously documented in vitro effect of antisense oligonucleotide, we believe that the proto-oncogene is involved in proliferation. The drug heparin and blood vessel wall heparan sulfates probably also inhibit SMC growth via suppression of c-myb. Thus, endothelial cell and SMC heparan sulfates appear to constitute a natural blood vessel wall antiproliferative pathway. To the best of our knowledge, these studies constitute the first reported use of antisense oligonucleotide to inhibit synthesis of a normal gene product under in vivo conditions with a subsequent effect upon a cellular process.(ABSTRACT TRUNCATED AT 250 WORDS)