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
Abstract
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: clowes@u.washington.edu
Web page maintained by: ruzzo /at/ cs /dot/ washington /dot/ edu