Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov...

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Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003

Transcript of Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov...

Page 1: Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003.

Chengpei Xu, MD, PhD

Hemodynamics and Vascular Remodeling Symposium

In Honor of Dr. Seymour GlagovThursday February 20, 2003

Page 2: Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday 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

Page 3: Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003.

Aortic wall structure

Page 4: Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003.

Characteristics of wall motion

Page 5: Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003.

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.

Page 6: Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003.

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

Page 7: Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003.

Reduction of aortic wall motion inhibitshypertension-mediated experimental atherosclerosis

No wrap Loose wrap

Firm wrap Control

Page 8: Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003.

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

Page 9: Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003.

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

Page 10: Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003.

Collage type I Collage type III Tropoelastin

Differential distribution of major ECM at the Proximal

Page 11: Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003.

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

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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

Page 12: Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003.

Cell proliferation BrdU incorporation rate increased

BrdU Incorporation Rate

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10

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60

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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

Page 13: Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003.

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

Page 14: Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003.

Apoptosis detected

LSCM, All nuclei were stained red with PI, and the nuclei of apoptotic cells were labeled green

Cell Apoptosis Rate

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5

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Ctrl 1D 3D 1W 2W 4W

Time Course

Nu

mb

er

of

Ap

op

toti

c C

ells

x *

* P<0.05 vs. Ctrl

Page 15: Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003.

Wall thickness increased

Aortic Wall Thickness

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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

Page 16: Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003.

PDGF-A expression upregulated

Relative mRNA Levels of PDGF-A

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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

Page 17: Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003.

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

Page 18: Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003.

Immuno-fluorescence staining of PDGF-A

Page 19: Chengpei Xu, MD, PhD Hemodynamics and Vascular Remodeling Symposium In Honor of Dr. Seymour Glagov Thursday February 20, 2003.

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