DIFFERENTIAL RESPONSE OF MESODERM-DERIVED AND NEURAL CREST-DERIVED SMOOTH-MUSCLE TO TGF-BETA-1 - REGULATION OF C-MYB AND ALPHA-1 (I) PROCOLLAGEN GENES

Previously, we demonstrated that avian vascular smooth muscle cells (V SMC) derived from embryonic abdominal and thoracic aorta grow differen tly in the presence of transforming growth factor beta (TGF-beta 1) an d platelet-derived growth factor (PDGF-BB) (Wrenn et al., In Vitro Cel l. Dev. Biol. 29, 73-78, 1992). The thoracic VSMC (N-VSMC) are derived from neural crest, and therefore differentiate from ectoderm; the abd ominal VSMC (M-VSMC) are derived from mesoderm. The present study was designed to identify factors that mediate the differential responses o f the VSMC to TGF-beta 1. We found that TGF-beta 1 increased DNA synth esis by approximately sevenfold in N-VSMC. Levels of both alpha 1 (I) procollagen and c-myb mRNAs were markedly induced in N-VSMC treated wi th TGF-beta 1. Chimeric plasmids containing up to 3.5 kb of alpha 1 (I ) procollagen 5' flanking DNA were induced to equivalent levels as pro collagen mRNA in N-VSMC. However, TGF-beta 1 increased DNA synthesis b y threefold in M-VSMC; there was no effect on alpha 1 (I) procollagen expression, and c-myb was not expressed, as demonstrated by immunohist ochemistry staining and RNA analyses. Antisense c-myb oligodeoxynucleo tides blocked the TGF-beta 1 induction of alpha 1 (I) procollagen and the growth of N-VSMC. The increase in DNA synthesis by M- and N-VSMC w as correlated with the secretion of PDGF-AA, and staurosporine and ant ibodies directed against PDGF-AA suppressed DNA synthesis, Our results demonstrate that TGF-beta 1 activity and c-myb expression modulate th e expression of alpha 1 (I) collagen and cell proliferation in neural crest-derived smooth muscle. The regulation of these events by TGF-bet a 1 may be important during morphogenesis of blood vessels and vascula r diseases. (C) 1997 Academic Press.