title: Bone morphogenetic protein 4: potential regulator of shear stress-induced graft neointimal atrophy.
abstract: OBJECTIVE
  Placement in baboons of a distal femoral arteriovenous fistula increases shear stress through aortoiliac polytetrafluoroethylene (PTFE) grafts and induces regression of a preformed neointima. Atrophy of the neointima might be controlled by shear stress-induced genes, including the bone morphogenetic proteins (BMPs). We have investigated the expression and function of BMPs 2, 4, and 5 in the graft neointima and in cultured baboon smooth muscle cells (SMCs).
  
  
  METHODS
  Baboons received bilateral aortoiliac PTFE grafts and 8 weeks later, a unilateral femoral arteriovenous fistula.
  
  
  RESULTS
  Quantitative polymerase chain reaction showed that high shear stress increased BMP2, 4, and 5 messenger RNA (mRNA) in graft intima between 1 and 7 days, while noggin (a BMP inhibitor) mRNA was decreased. BMP4 most potently (60% inhibition) inhibited platelet-derived growth factor-stimulated SMC proliferation compared with BMP2 and BMP5 (31% and 26%, respectively). BMP4 also increased SMC death by 190% +/- 10%. Noggin reversed the antiproliferative and proapoptotic effects of BMP4. Finally, Western blotting confirmed BMP4 protein upregulation by high shear stress at 4 days. BMP4 expression demonstrated by in situ hybridization was confined to endothelial cells.
  
  
  CONCLUSIONS
  Increased BMPs (particularly BMP4) coupled with decreased noggin may promote high shear stress-mediated graft neointimal atrophy by inhibiting SMC proliferation and increasing SMC death.
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98195-6410, USA.
authors.forename: Patrick C H
authors.initials: PC
authors.lastname: Hsieh
authors.forename: Richard D
authors.initials: RD
authors.lastname: Kenagy
authors.forename: Eileen R
authors.initials: ER
authors.lastname: Mulvihill
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Jeanette
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Cindy M C
authors.initials: CM
authors.lastname: Chang
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Yao
authors.forename: Walter L
authors.initials: WL
authors.lastname: Ruzzo
authors.forename: Suzanne
authors.initials: S
authors.lastname: Justice
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Hudkins
authors.forename: Charles E
authors.initials: CE
authors.lastname: Alpers
authors.forename: Scott
authors.initials: S
authors.lastname: Berceli
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Clowes
mesh_terms: D000818:Animals; D001284:Atrophy / Q000209:etiology; D001807:Blood Vessel Prosthesis; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D008297:Male; D010215:Papio; D033081:Shear Strength; D013314:Stress, Mechanical; D017539:Tunica Intima / Q000473:pathology*
chemical_list: D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins