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Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003. Chengpei Xu, MD, PhD. Aortic Coarctation-Induced Vascular Wall Remodeling. Introduction. Vascular wall responds to hemodynamic alteration - PowerPoint PPT Presentation
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Chengpei Xu, MD, PhD
Hemodynamics and Vascular Remodeling Symposium
In Honor of Dr. Seymour GlagovThursday February 20, 2003
Introduction
• Vascular wall responds to hemodynamic alteration
• Hypertension induces vascular wall remodeling
• Aortic coarctation results in Bp, wall motion, wall
thickening, lesion prone Proximally
Bp, Complex wall motion, PSD, lesion resistant Distally
(Lyon, Runyon-Hass, Davis, Glagov and Zarins. JVS, 5(1):59-67, 1987)
75% lumen reduction
Aortic wall structure
Characteristics of wall motion
Lyon, Runyon-Hass, Davis, Glagov and Zarins. JVS, 5(1):59-67, 1987
Xu, Zarins, Pannaraj, Bassiouny, Glagov. Arterioscler Thromb Vasc Biol. 2000 Dec;20(12):2566-2572.
Reduction of aortic wall motion by wrapping the aorta in rabbits
Materials and Methods
Coarctation + PTFE wrapping + dietWall motion by ultrasound systemWall motion=% of lumen at A, B, C, DSection
[Tropea and Zarins et al. Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):2127-33]
Levels A B C D
Firm wrap loose wrap
Reduction of aortic wall motion inhibitshypertension-mediated experimental atherosclerosis
No wrap Loose wrap
Firm wrap Control
Prox: Up regulation of gene expression for collagen types I and III
Molecular mechanisms in the coarctation induced remodeling (1)
Dist: At the PSD, gene expression for collagen was not remarkable
Collagen type I Collagen type III
[Xu, Zarins, Bassiouny, Briggs, Reardon, Glagov. J Vasc Res. 2000 May-Jun;37(3):170-82.]
* P<0.05 vs. Ctrl* P<0.05 vs. Ctrl
Tropoelastin gene expression
Dist: BiphasicProx: Increase
Xu, Zarins, Glagov. J Vasc Surg. 2002 Sep;36(3):605-612 Xu, Zarins, Glagov. Exp Mol Pathol. 2002 Apr;72(2):115-23
* P<0.05 vs. Ctrl * P<0.05 vs. Ctrl
Collage type I Collage type III Tropoelastin
Differential distribution of major ECM at the Proximal
TGF-1 and 3 genes upregulated
*
Molecular Bases in Vessel Remodeling (2)
Relative mRNA Levels of TGF 1 and 3
0.00
0.10
0.20
0.30
0.40
0.50
0.60
Ctrl 1D 3D 1W 2W 4W
Time Course
Rat
io o
f Den
sity
TGF beta-1
TGF beta-3*
**
Protein Levels of TGF-1 and 3
0.00
0.50
1.00
1.50
2.00
2.50
Ctrl 1D 3D 1W 2W 4W
Time Course
TGF -b1
TGF -b3 *
* *
Xu, Lee, Singh, Sho, Li, Sho, Masuda, Zarins. J Vasc Surg. 2001 Mar;33(3):570-578
* P<0.05 vs. Ctrl * P<0.05 vs. Ctrl
Cell proliferation BrdU incorporation rate increased
BrdU Incorporation Rate
0
10
20
30
40
50
60
70
80
90
Ctrl 1 D 3 D 1 W 2 W 4 W
Time Course
Nu
mb
er
of
La
be
led
Nu
cle
i **
*
* P<0.05 vs. Ctrl
Some apoptosis related cytokines - decreased expression
Relative mRNA Levels of Bcl-xS and FasL
0.00
0.10
0.20
0.30
0.40
0.50
Ctrl 1D 3D 1W 2W 4W
Time Course
Ra
tio o
f De
nsi
ty Bcl-xS
FasL
** *
*
*
*
Protein Levels of Bcl-xS and FasL
0.00
2.00
4.00
6.00
8.00
Ctrl 1D 3D 1W 2W 4W
Time CourseD
ensi
tom
etry
Val
ues Bcl-xS
FasL
*
**
**
*
*
*
* P<0.05 vs. Ctrl * P<0.05 vs. Ctrl
Apoptosis detected
LSCM, All nuclei were stained red with PI, and the nuclei of apoptotic cells were labeled green
Cell Apoptosis Rate
0
5
10
15
20
25
30
35
Ctrl 1D 3D 1W 2W 4W
Time Course
Nu
mb
er
of
Ap
op
toti
c C
ells
x *
* P<0.05 vs. Ctrl
Wall thickness increased
Aortic Wall Thickness
0.00
0.04
0.08
0.12
0.16
1 D 3 D 1 W 2 W 4 W
Time Course
Me
as
ure
me
nt
(mm
)Normo-tensiveHypertensive
* * *
* P<0.05 vs. Ctrl
PDGF-A expression upregulated
Relative mRNA Levels of PDGF-A
0.00
0.20
0.40
0.60
0.80
1.00
Ctrl 1d 3d 1w 2w 4w 8w
Time Course
Ra
tio o
f P
DG
F-A
/GA
PD
H * **
* P<0.05 vs. Ctrl
Protein Levels of PDGF-A
0.00.51.01.52.02.53.03.54.04.5
Ctrl 1d 3d 1w 2w 4w 8w
Time course
value
***
* P<0.05 vs. Ctrl
Immuno-fluorescence staining of PDGF-A
Summary
Coarctation-induced remodeling involves:
Wall motion - accelerating atherosclerosis
ECM gene expression & differential deposition
Tropoelastin regulation more at the PSD
A coordinated regulation of cell proliferation and cell death, governing the remodeling