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. CLINICAL RELEVANCE: Pharmacologic therapy to prevent luminal stenosis or restenosis after vascular reconstruction is directed at inhibiting intimal hyperplasia and smooth muscle cell growth. An alternative approach might be to induce intimal atrophy after luminal narrowing has developed. This approach would be particularly useful for treating stenosis in stented vessels or synthetic bypass grafts because intimal hyperplasia is the only mechanism for luminal narrowing. Furthermore, it would permit the physician to treat the population of patients (about 30%) who actually develop a problem with stenosis or restenosis. We have previously provided proof of principle that an established neointima can be induced to atrophy in baboon polytetrafluoroethylene grafts, but not in normal artery, by simply switching from normal to high blood flow and shear stress. In this study, we provide evidence that members of the bone morphogenetic protein family may play a role in this neointimal atrophy.