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