Activated alpha 2-macroglobulin and transforming growth factor-beta 1 induce a synergistic smooth muscle cell proliferative response.
The role that soluble binding proteins might play in regulating transforming growth factor-beta 1 (TGF-beta 1)-induced growth of smooth muscle cells (SMC) is unknown. alpha 2-Macroglobulin (alpha 2M) is the major plasma binding protein for TGF-beta. Reaction of alpha 2M with methylamine (alpha 2M-MA) forms "activated" alpha 2M which binds TGF-beta and specific cell surface receptors. The objectives of these studies were to determine whether native alpha 2M or alpha 2M-MA influences growth responses of cultured rat aortic SMC to TGF-beta 1. Results demonstrated that native alpha 2M was not mitogenic. Treatment with alpha 2M-MA or TGF-beta 1 stimulated a 3- or 3.5-fold increase in [3H]thymidine incorporation, respectively. Cotreatment with TGF-beta 1 and alpha 2M-MA resulted in a 70-fold increase in [3H]thymidine incorporation. SMC bound alpha 2M-MA in a specific and saturable manner and expressed alpha 2M receptor/low density lipoprotein receptor-related protein (LRP). A modified form of alpha 2M-MA (alpha 2M-MA-cis-dichlorodiammine platinum), which bound TGF-beta 1 but did not bind alpha 2M receptors, failed to enhance TGF-beta 1-induced growth. In summary, results demonstrated that alpha 2M-MA enhanced TGF-beta 1-induced growth responses and that this effect was dependent on alpha 2M-MA binding to alpha 2M receptor/LRP.
Stouffer
G A
GA
Department of Medicine, University of Virginia School of Medicine, Charlottesville 22908.
LaMarre
J
J
Gonias
S L
SL
Owens
G K
GK
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004357:Drug Synergism; D007700:Kinetics; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008934:Mitogens / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000302:isolation & purification / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D000511:alpha-Macroglobulins / Q000378:metabolism / Q000494:pharmacology*
D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008934:Mitogens; D011971:Receptors, Immunologic; D016212:Transforming Growth Factor beta; D000511:alpha-Macroglobulins; D004247:DNA; D013936:Thymidine