BMP4: Potential Regulator of Shear Stress-induced Graft Neointimal Atrophy

Patrick C.H. Hsieh, MD; Richard D. Kenagy, PhD; Eileen R. Mulvihill, PhD; Joseph P. Jeanette, DO; Xi Wang, MD, PhD; Cindy M.C. Chang, MS; Zizhen Yao, MS; Walter L. Ruzzo, PhD; Suzanne Justice, BS; Kelly L. Hudkins, MS; Charles E. Alpers, MD; Scott Berceli, MD; Alexander W. Clowes, MD

From the Departments of Bioengineering (PCHH), Surgery (PCHH, RDK, CMCC, SH, AWC), Computer Science and Engineering (ZY, WLR) and Pathology (XW, ERM, KLH, CEA, AWC), University of Washington, Seattle, WA

Appeared in: Journal of Vascular Surgery 2006 January; 43(1): 150-158.

Objective: Placement in baboons of a distal femoral arteriovenous fistula increases shear stress (SS) through aorto-iliac polytetrafluoroethylene (PTFE) grafts and induces regression of a preformed neointima. Atrophy of the neointima might be controlled by SS-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.
Methods and Results: Baboons received bilateral aortoiliac PTFE grafts and eight weeks later a unilateral femoral arteriovenous fistula. Quantitative PCR showed that high SS increased BMP2, 4 and 5 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 to BMP2 and 5 (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 SS at 4 days. BMP4 expression as demonstrated by in situ hybridization was confined to endothelial cells.
Conclusions: Increased BMPs, particularly BMP4, coupled with decreased noggin may promote high SS mediated graft neointimal atrophy by inhibiting SMC proliferation and increasing SMC death.

Keywords: BMP4, shear stress, noggin, neointimal hyperplasia, cell death

Supplementary Data

We provide here links to three Excel workbooks containing data from days 1, 3, and 7 post-surgery, resp., as well as a workbook showing significantly changed genes categorized by function:
Correspondence to Alexander W. Clowes, MD, Department of Surgery, University of Washington, PO box 356410, 1959 N.E. Pacific St., Seattle, Washington 98195-6410. Email:

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