Atherosclerosis

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Atherosclerosis
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Atheroma are not merely filled with lipid, but
contain cells whose functions critically
influence atherogenesis

• Intrinsic Vascular Wall Cells
• Endothelium
• Smooth Muscle Cells
• Inflammatory Cells
• Macrophages
• T Lymphocytes
• Mast Cells

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Cell Types in the Human Atheroma
Monocyte/Macrophage
Endothelium
Intima
TunicaMedia
T-lymphocytes
Smooth musclecells
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Schematic Time Course of Human Atherogenesis
Ischemic HeartDisease
CerebrovascularDisease
Peripheral VascularDisease
Lesion initiation
No symptoms
Symptoms
Symptoms
Time (y)
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Macrophage Functions in Atherogenesis
Attachment
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LeukocyteEndothelial Adhesion Molecules
Mono
T
PMN
B
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Vascular Cell Adhesion Molecule 1(VCAM-1)

• Binds monocytes and lymphocytes- Cells found in
  atheroma
• Expressed by endothelium over nascent fatty
  streaks
• Expressed by microvessels of the mature atheroma

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An atherogenic diet rapidly induces VCAM-1, a
cytokine-regulatable mononuclear leukocyte
adhesion molecule, in rabbit aortic endothelium
Li H et al. Arterioscler Thromb 199313197-204.
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VCAM-1 Expression in Rabbit Aorta
3 weeks on atherogenic diet
Li H et al. Arterioscler Thromb 199313197-204.
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Macrophage Functions in Atherogenesis
Penetration
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Monocyte Chemoattractant Protein 1(MCP-1)

• A potent mononuclear cell chemoattractant
• Produced by endothelial and smooth muscle cells
• Localizes in human and experimental atheroma

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Absence of monocyte chemoattractant protein-1
reduces atherosclerosis in low-density
lipoprotein receptordeficient mice
Gu L et al. Mol Cell 19982275-281.
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Reduced Lipid Deposition in MCP-1Deficient
Atherosclerotic Mice
LDL-R /MCP-1 /
LDL-R /MCP-1 /
Gu L et al. Mol Cell 19982275-281.
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Reduced Lipid Deposition in MCP-1Deficient
Atherosclerotic Mice
Oil Red Staining Aortic Surface Stained


/
-/-
/
-/-
Time on Diet
12 14 weeks
20 25 weeks
P 0.001 compared to /p 0.005 compared
to /
Gu L et al. Mol Cell 19982275-281.
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Macrophage Functions in Atherogenesis
Activation
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Macrophage Functions in Atherogenesis
Division
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Macrophage Colony-Stimulating Factor (M-CSF)

• A potent monocyte activator and co-mitogen
• Produced by endothelial and smooth muscle cells
• Localizes in human and experimental atheroma

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Augmented M-CSF gene expression in human and
experimental atherogenesis
Rosenfeld ME et al. Am J Pathol
1992140291-300. Clinton SK et al. Am J Pathol
1992140301-316.
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M-CSF Expression in Atheroma
IntimalM-CSFinAtheroma
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M-CSF Promotes Atherogenesis
Smith JD et al. Decreased atherosclerosis in
mice deficient in both macrophage
colony-stimulating factor (op) and apolipoprotein
E. Proc Natl Acad Sci U S A 1995928264-8268. Qi
ao JH et al. Role of macrophage
colony-stimulating factor in atherosclerosis
studies of osteopetrotic mice. Am J Pathol
19971501687-1699. Rajavashisth T et al.
Heterozygous osteopetrotic (op) mutation reduces
atherosclerosis in LDL receptordeficient mice. J
Clin Invest 19981012702-2710.
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M-CSF Deficiency (op mutation) Reduces Atheroma
in LDL ReceptorKnockout Mice
/
op/
op/op
Rajavashisth T et al. J Clin Invest
19981012702-2710.
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M-CSF Gene Dosage Relates to Atheroma Size in
LDLR / Mice
107
106
Fatty Lesions in Aortic Root(?m2/section)
105
104
103
op/
/
op/op
Genotype
Rajavashisth T et al. J Clin Invest
19981012702-2710.
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Molecular Mediators of Atherogenesis
VCAM-1
MCP-1
M-CSF
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Anatomy of the Atherosclerotic Plaque
Fibrous cap
Lumen
Shoulder
Lipid Core
Intima
Internal
Elastic laminæ
Media
External
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Schematic Time Course of Human Atherogenesis
Ischemic HeartDisease
CerebrovascularDisease
Peripheral VascularDisease
Transition from chronic to acute atheroma
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Thrombosis of a Disrupted Atheroma, the Cause of
Most Acute Coronary Syndromes, Results from

• Weakening of the fibrous cap
• Thrombogenicity of the lipid core

Illustration courtesy of Michael J. Davies, M.D.
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Matrix Metabolism and Integrity of the Plaques
Fibrous Cap
Synthesis
Breakdown
Fibrouscap
Collagen-degrading Proteinases
IFN-?

CD-40L




IL-1TNF-?MCP-1M-CSF


Tissue Factor Procoagulant
Lipid core
Libby P. Circulation 1995912844-2850.
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Increased Expression of Interstitial Collagenase
(CL) by Smooth Muscle Cells (SMC) and Macrophages
(M?) in Human Atheroma
Galis ZS et al. J Clin Invest 1994942493-2503.
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Plaque Rupture with Thrombosis
Fibrous cap
Thrombus
1 mm
Lipid core
Illustration courtesy of Frederick J. Schoen,
M.D., Ph.D.
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Thrombosis of a Disrupted Atheroma, the Cause of
Most Acute Coronary Syndromes, Results from

• Weakening of the fibrous cap
• Thrombogenicity of the lipid core

Illustration courtesy of Michael J. Davies, M.D.
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CD40 and Tissue Factor in Atheroma
CD40
Tissue Factor
Mach F et al. Circulation 199796396-399.
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CD40 Ligation Induces Tissue Factor Expression in
Human Monocyte-Derived Macrophages
160 120 80 40 0
160 120 80 40 0
T cell/membranes/?-CD40L
rCD40L/?-CD40L
T cell/membranes
rCD40L
Cell Numbers
100
101
102
103
100
101
102
103
Log Fluorescence
Mach F et al. Circulation 199796396-399.
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CD40 ligand on activated platelets triggers an
inflammatory reaction of endothelial cells
Henn V et al. Nature 1998391591-594.
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Inflammation Can Promote Thrombosis
Fibrinogen
Via gp llb/llla
TissueFactor
Platelet-FibrinThrombus
CD40L
Fibrinopeptides
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Inflammation Participates in All Phases of
Atherothrombotic Disease

• Lesion initiation
• Lesion progression
• Thrombotic complications

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Thanks