title: Endothelial Bmp4 is induced during arterial remodeling: effects on smooth muscle cell migration and proliferation.
abstract: BACKGROUND
  Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta superfamily of proteins that have multiple functional roles in mammalian development. A role for BMP4 in adult vascular remodeling has recently been suggested. We evaluated the expression of Bmp4 during neointimal lesion development in vivo.
  
  
  METHODS
  Heterozygous Bmp4(lacZ/+) mice were used to evaluate in vivo Bmp4 expression after carotid ligation. beta-galactosidase (beta-gal) activity was evaluated in histological sections 1 to 14 d after carotid ligation and this was compared with control carotid arteries. The effects of recombinant human (rh) BMP4 on smooth muscle cell (SMC) migration and proliferation were evaluated using a rat aortic SMC line. We next assessed the effects of BMP4 signaling by over-expressing a constitutively active BMP receptor (BMPR-IA/Alk-3) using adenovirus-mediated gene transfer. SMC proliferation, migration, and apoptosis were evaluated in adenovirus transfected cells.
  
  
  RESULTS
  Ligated carotid arteries expressed endothelium-specific beta-gal staining after 1 d. Staining intensity increased at both 3 d and 1 wk after ligation and remained stable at 2 weeks while no beta-gal staining was observed in control vessels. Endothelial-specific expression of beta-galactosidase was confirmed through positive staining for PECAM-1. When human recombinant BMP4 was added to cultured SMCs, it inhibited migration but did not affect cultured SMC proliferation. SMCs infected with adenovirus encoding for the active BMP receptor Alk-3 demonstrated dose-dependent receptor expression. Alk-3 over-expressing cells showed a dose-dependent decrease in proliferation and migration but no effect on apoptosis.
  
  
  CONCLUSIONS
  These results demonstrate that endothelial Bmp4 expression is upregulated after carotid ligation in vivo, and furthermore, that activating the BMP signaling cascade results in decreased SMC proliferation and migration. This suggests that BMPs may counterbalance the effect of mitogen up-regulation observed during the development of neointimal hyperplasia.
authors: Division of Vascular Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors: Matthew A
authors: MA
authors: Corriere
authors: Chris M
authors: CM
authors: Rogers
authors: Jonathan L
authors: JL
authors: Eliason
authors: Jimbob
authors: J
authors: Faulk
authors: Tsutomu
authors: T
authors: Kume
authors: Brigid L M
authors: BL
authors: Hogan
authors: Raul J
authors: RJ
authors: Guzman
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D055415:Bone Morphogenetic Protein 4; D052004:Bone Morphogenetic Protein Receptors / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism*; D008026:Ligation; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; C525811:Bmp4 protein, rat; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D052004:Bone Morphogenetic Protein Receptors; D001616:beta-Galactosidase
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