Bone morphogenetic protein 4: potential regulator of shear stress-induced graft neointimal atrophy.
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.
Hsieh
Patrick C H
PC
Department of Bioengineering, University of Washington, Seattle, WA 98195-6410, USA.
Kenagy
Richard D
RD
Mulvihill
Eileen R
ER
Jeanette
Joseph P
JP
Wang
Xi
X
Chang
Cindy M C
CM
Yao
Zizhen
Z
Ruzzo
Walter L
WL
Justice
Suzanne
S
Hudkins
Kelly L
KL
Alpers
Charles E
CE
Berceli
Scott
S
Clowes
Alexander W
AW
D000818:Animals; D001284:Atrophy / Q000209:etiology; D001807:Blood Vessel Prosthesis; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D008297:Male; D010215:Papio; D033081:Shear Strength; D013314:Stress, Mechanical; D017539:Tunica Intima / Q000473:pathology*
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins