The Change of Blood Stream Dynamics Promote Vein Grafts
Remodeling and Rapamycin Inhibits Neointimal
Hyperplasia in Experimental Vein Grafts
Background For patients with coronary artery disease or the most severe
manifestations of lower extremity arterial occlusive disease, bypass surgery using
autogenous vein has been the most durable reconstruction. However, the incidence of
bypass graft stenosis and graft failure remains substantial and wholesale
improvements in patency are lacking. One potential explanation is that stenosis arises
not only from over exuberant intimal hyperplasia, but also due to insufficient
adaptation or remodeling of the vein to the arterial environment. In order to adapt to
the arterial environment, the limited formation of intimal hyperplasia in the vein graft
wall is thought to be an important component of successful vein graft adaptation.
However, it is also known that abnormal,or uncontrolled, adaptation may lead to
abnormal vessel wall remodeling with excessive neointimal hyperplasia,and
ultimately vein graft failure and clinical complications. Therefore, understanding the
venous-specific pathophysiological and molecular mechanisms of vein graft
adaptation are important for clinical vein graft management. It was known that many
growth factors and hormone contribute to the newointimal hyperplasia.The GFs and
hormone stimulate mTOR through the PI3K/Akt pathway. Rapamycin is an
immunosuppressive agent,blocks cell cycle progression by forming a complex with
the immunophilin FK506-binding protein 12 (FKBP12). This complex inhibits mTOR,
resulting in an arrest at the G1-phase of the cell cycle. Rapamycin coated stents have
been demonstrated to suppress restenosis in experimental and clinical studies of
percutaneous coronary catheter intervention.
Objective To investigate the dynamic changes of vascular intimal and smooth
muscle cell (SMC) proliferation and collagen distribution in the vein graft restenosis
mode1 of mice and evaluate the effects of intimal，cell proliferation and collagen
distribution on vascular remodeling. Investigate whether rapamycin can reduce
neointima formation in a mouse model of vein graft disease.
Method C57BL6J mice underwent interposition of the inferior vena cava from
isogenic donor mice into the common carotid artery using a previously described cuff
technique. In the treatment group 200 ug of rapamycin was applied locally in pluronic
gel. The control group did not receive local treatment. Grafts were harvested at 1, 2, 4,
and 6 weeks and underwent morphometric
analysis as well as immunohistochemical analysis.
Results ①Under the arterial circulation , in the control group at 1 week after
operation，the neointima formed and continuously thickened,whose thickness reached
maximal at 6 weeks after operation.The thickness and cell density of adventitia
increased gradually at 1 week,which reached peak at 4 weeks after operation．But in
the 6 weeks group ,they were smaller than those in the 4 weeks group．According to
PCNA stain．the proliferation index of adventitia cell and SMC increased significantly
at 2 weeks after operation，which reached peak at 4 weeks,whereas the expression of
PCNA reverted toward the baseline at 6 weeks after operation.②At 2weeks after
operation，the collagen of adventitia and neointima gradually increased.The collagen
of adventitia reached maximal at 4 weeks .But at 6 weeks,they were smaller than
those at 4 weeks after operation (P<0.05). ③The luminal area and internal elastic
lamina gradually decreased after operation, which in the 4 weeks reduced
significantly compared with the 1 week group and 2 weeks group(P<0.05).But the
residual restenosis rate changed inversely compared with the luminal
area．Remodeling index and extemal elastic lamina slightly increased at the 1 week
group,but reduced gradually after that.which in the 4weeks and 6 weeks group
decreased significantly (P<0.05). ④In grafted veins without treatment
(controls),median intimal thickness was 9.6 (6.4 to 29)um, 11.9 (7.9to 39.9)um, 46.6
(12.4 to 57.7)um, and 57.5 (32.5 to 71.1)um after 1, 2, 4, and 6 weeks, respectively. In
the 200 ug rapamycin treatment group the intimal thickness was 4.3 (3.4 to5.6)um, 3.8
(3.2 to 6.3)um, 17.1 (4.8 to 63)um, and 33.9 (11.3to 80.3)um after 1, 2, 4, and 6
weeks, respectively. This difference of intimal thickness of 200ug treated animals
compared with controls was statistically significant at 1and 2 weeks.
Immunohistochemically the reduction of intimal thickness was associated with a
decreased amount of expression of PCNA and SMA positive cells in the rapamycin
treated grafts.
Conclusion The changes of vascular adventitia and smooth muscle cell
proliferation,the thickness and fibration of adventitia and rearrangement of collagen
are the important factors on intimal hyperplasia and vascular remodeling,whieh takes
part in and accelerate the course of vein restenosis. Perivascular application of
rapamycin inhibits neointimal hyperplasia of vein grafts in a mouse model. These
results suggest that rapamycin may have a therapeutic potential for the treatment of
vein graft disease.
Keywords Blood Stream Dynamics; Vein Grafts Remodeling; Intimal
Hyperplasia;Veingraft model; Rapamycin