TitleBone morphogenetic protein 4: potential regulator of shear stress-induced graft neointimal atrophy.
Publication TypeJournal Article
Year of Publication2006
AuthorsHsieh PCH, Kenagy RD, Mulvihill ER, Jeanette JP, Wang X, Chang CMC, Yao Z, Ruzzo WL, Justice S, Hudkins KL, Alpers CE, Berceli S, Clowes AW
JournalJournal of vascular surgery : official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
Date or Month Published2006 Jan
KeywordsAnimals, Atrophy, Blood Vessel Prosthesis, Bone Morphogenetic Protein 4, Bone Morphogenetic Proteins, Male, Papio, Shear Strength, Stress, Mechanical, Tunica Intima
AbstractOBJECTIVE: 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.
Alternate JournalJ. Vasc. Surg.
Citation Key1882
PubMed ID16414402