chengpei xu, md, phd hemodynamics and vascular remodeling symposium in honor of dr. seymour glagov...
TRANSCRIPT
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