ACTIVATED ALPHA-2-MACROGLOBULIN AND TRANSFORMING GROWTH-FACTOR-BETA-1INDUCE A SYNERGISTIC SMOOTH-MUSCLE CELL PROLIFERATIVE RESPONSE

The role that soluble binding proteins might play in regulating transf orming growth factor-beta1 (TGF-beta1)-induced growth of smooth muscle cells (SMC) is unknown. Alpha2-macroglobulin (alpha2M) is the major p lasma binding protein for TGF-beta. Reaction of alpha2M with methylami ne (alpha2M-MA) forms ''activated'' alpha2M which binds TGF-beta and s pecific cell surface receptors. The objectives of these studies were t o determine whether native alpha2M or alpha2M-MA influences growth res ponses of cultured rat aortic SMC to TGF-beta1. Results demonstrated t hat native alpha2M was not mitogenic. Treatment with alpha2M-MA or TGF -beta1 stimulated a 3- or 3.5-fold increase in [H-3]thymidine incorpor ation, respectively. Cotreatment with TGF-beta1 and alpha2M-MA resulte d in a 70-fold increase in [H-3]thymidine incorporation. SMC bound alp ha2M-MA in a specific and saturable manner and expressed alpha2M recep tor/low density lipoprotein receptor-related protein (LRP). A modified form of alpha2M-MA (alpha2M-MA-cis-dichlorodiammine platinum), which bound TGF-beta1 but did not bind alpha2M receptors, failed to enhance TGF-beta1-induced growth. In summary, results demonstrated that alpha2 M-MA enhanced TGF-beta1-induced growth responses and that this effect was dependent on alpha2M-MA binding to alpha2M receptor/LRP.