Bone morphogenetic protein 4: potential regulator of shear stress-induced graft neointimal atrophy

J Vasc Surg. 2006 Jan;43(1):150-8. doi: 10.1016/j.jvs.2005.08.008.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Atrophy / etiology
  • Blood Vessel Prosthesis*
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Proteins / physiology*
  • Male
  • Papio
  • Shear Strength
  • Stress, Mechanical
  • Tunica Intima / pathology*


  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Proteins