![Page 1: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/1.jpg)
Atherosclerosis Atherosclerosis
![Page 2: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/2.jpg)
Atheroma are not merely filled with lipid, Atheroma are not merely filled with lipid, but contain cells whose functions critically but contain cells whose functions critically influence atherogenesis:influence atherogenesis:
Intrinsic Vascular Wall Cells:
Endothelium
Smooth Muscle Cells
Inflammatory Cells:
Macrophages
T Lymphocytes
Mast Cells
![Page 3: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/3.jpg)
Cell Types in the Human AtheromaCell Types in the Human Atheroma
Monocyte/Monocyte/MacrophageMacrophage
T-lymphocytesT-lymphocytesTunicaMedia
Intima
Smooth musclecells
EndotheliumEndothelium
![Page 4: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/4.jpg)
No No symptomssymptoms ++ Symptoms Symptoms
Schematic Time Course of Human Schematic Time Course of Human AtherogenesisAtherogenesis
Time (y)Time (y)
SymptomsSymptoms
Lesion initiationLesion initiation
Ischemic HeartIschemic HeartDiseaseDisease
CerebrovascularCerebrovascularDiseaseDisease
Peripheral VascularPeripheral VascularDiseaseDisease
![Page 5: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/5.jpg)
Macrophage Functions in AtherogenesisMacrophage Functions in Atherogenesis
AttachmentAttachment
![Page 6: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/6.jpg)
Leukocyte–Endothelial Adhesion MoleculesLeukocyte–Endothelial Adhesion Molecules
MonoMonoTT
BB PMNPMN
![Page 7: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/7.jpg)
Vascular Cell Adhesion Molecule 1Vascular Cell Adhesion Molecule 1(VCAM-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
![Page 8: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/8.jpg)
An atherogenic diet rapidly induces An atherogenic diet rapidly induces
VCAM-1, a cytokine-regulatable VCAM-1, a cytokine-regulatable
mononuclear leukocyte adhesion mononuclear leukocyte adhesion
molecule, in rabbit aortic endotheliummolecule, in rabbit aortic endothelium
Li H et al. Arterioscler Thromb 1993;13:197-204.
![Page 9: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/9.jpg)
VCAM-1 Expression in Rabbit AortaVCAM-1 Expression in Rabbit Aorta
Li H et al. Arterioscler Thromb 1993;13:197-204.
3 weeks on atherogenic diet
![Page 10: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/10.jpg)
PenetrationPenetration
Macrophage Functions in AtherogenesisMacrophage Functions in Atherogenesis
![Page 11: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/11.jpg)
Monocyte Chemoattractant Protein 1Monocyte Chemoattractant Protein 1(MCP-1)(MCP-1)
A potent mononuclear cell chemoattractant
Produced by endothelial and smooth muscle cells
Localizes in human and experimental atheroma
![Page 12: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/12.jpg)
Absence of monocyte chemoattractant Absence of monocyte chemoattractant
protein-1 reduces atherosclerosis in protein-1 reduces atherosclerosis in
low-density lipoprotein receptor–low-density lipoprotein receptor–
deficient micedeficient mice
Gu L et al. Mol Cell 1998;2:275-281.
![Page 13: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/13.jpg)
Reduced Lipid Deposition in MCP-1–Reduced Lipid Deposition in MCP-1–Deficient Atherosclerotic MiceDeficient Atherosclerotic Mice
Gu L et al. Mol Cell 1998;2:275-281.
LDL-R –/–LDL-R –/–
MCP-1 +/+MCP-1 +/+
LDL-R –/–LDL-R –/–
MCP-1 –/–MCP-1 –/–
![Page 14: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/14.jpg)
Gu L et al. Mol Cell 1998;2:275-281.
Reduced Lipid Deposition in MCP-1–Reduced Lipid Deposition in MCP-1–Deficient Atherosclerotic MiceDeficient Atherosclerotic Mice
0
5
10
15
20
25
30
Oil
Red S
tain
ing
% A
ort
ic S
urf
ace
Sta
ined
Time on Diet: 12 – 14 weeks
+/+ -/-
***
+/+ -/-
20 – 25 weeks *P = 0.001 compared to +/+**p = 0.005 compared to +/+
![Page 15: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/15.jpg)
Macrophage Functions in AtherogenesisMacrophage Functions in Atherogenesis
Activation
![Page 16: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/16.jpg)
Macrophage Functions in AtherogenesisMacrophage Functions in Atherogenesis
Division
![Page 17: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/17.jpg)
Macrophage Colony-Stimulating Factor Macrophage Colony-Stimulating Factor (M-CSF)(M-CSF)
A potent monocyte activator and co-mitogen
Produced by endothelial and smooth muscle cells
Localizes in human and experimental atheroma
![Page 18: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/18.jpg)
Augmented M-CSF gene expression in Augmented M-CSF gene expression in
human and experimental atherogenesishuman and experimental atherogenesis
Rosenfeld ME et al. Am J Pathol 1992;140:291-300.Clinton SK et al. Am J Pathol 1992;140:301-316.
![Page 19: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/19.jpg)
M-CSF Expression in AtheromaM-CSF Expression in Atheroma
IntimalM-CSF
inAtheroma
![Page 20: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/20.jpg)
M-CSF Promotes AtherogenesisM-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 1995;92:8264-8268.
Qiao JH et al. Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice. Am J Pathol 1997;150:1687-1699.
Rajavashisth T et al. Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor–deficient mice. J Clin Invest 1998;101:2702-2710.
![Page 21: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/21.jpg)
M-CSF Deficiency (M-CSF Deficiency (opop mutation) Reduces mutation) Reduces Atheroma in LDL Receptor–Knockout MiceAtheroma in LDL Receptor–Knockout Mice
Rajavashisth T et al. J Clin Invest 1998;101:2702-2710.
+/++/+ op/+op/+ op/opop/op
![Page 22: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/22.jpg)
M-CSF Gene Dosage Relates to Atheroma M-CSF Gene Dosage Relates to Atheroma Size in LDLR –/– MiceSize in LDLR –/– Mice
Rajavashisth T et al. J Clin Invest 1998;101:2702-2710.
107
Fatt
y L
esi
ons
in A
ort
ic R
oot
(m
2/s
ect
ion) 106
105
104
103
(10)* (4)
*
(12)
Genotypeop/++/+ op/op
![Page 23: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/23.jpg)
Molecular Mediators of AtherogenesisMolecular Mediators of Atherogenesis
M-CSFMCP-1
VCAM-1
![Page 24: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/24.jpg)
Anatomy of the Atherosclerotic PlaqueAnatomy of the Atherosclerotic Plaque
LumenLipidCore
Fibrous cap
Shoulder
Intima
MediaElasticlaminæ
Internal
External
![Page 25: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/25.jpg)
Schematic Time Course of Human Schematic Time Course of Human AtherogenesisAtherogenesis
Transition from chronic to acute atheromaTransition from chronic to acute atheroma
Ischemic HeartIschemic HeartDiseaseDisease
CerebrovascularCerebrovascularDiseaseDisease
Peripheral VascularPeripheral VascularDiseaseDisease
![Page 26: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/26.jpg)
Thrombosis of a Disrupted Atheroma, the Thrombosis of a Disrupted Atheroma, the Cause of Most Acute Coronary Cause of Most Acute Coronary Syndromes, Results from:Syndromes, Results from:
Weakening of Weakening of the fibrous capthe fibrous cap
Thrombogenicity of the lipid core
Illustration courtesy of Michael J. Davies, M.D.
![Page 27: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/27.jpg)
Matrix Metabolism and Integrity of the Matrix Metabolism and Integrity of the Plaque’s Fibrous CapPlaque’s Fibrous Cap
Libby P. Circulation 1995;91:2844-2850.
+ + + +
++
–
Synthesis Breakdown
Lipid core
IL-1TNF-MCP-1M-CSF
FibrouscapIFN-IFN-
CD-40L
Collagen-degradingCollagen-degradingProteinasesProteinases
Tissue FactorTissue FactorProcoagulantProcoagulant
![Page 28: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/28.jpg)
Increased Expression of Interstitial Increased Expression of Interstitial Collagenase (CL) by Smooth Muscle Cells Collagenase (CL) by Smooth Muscle Cells (SMC) and Macrophages (M(SMC) and Macrophages (M) in Human ) in Human AtheromaAtheroma
Galis ZS et al. J Clin Invest 1994;94:2493-2503.
![Page 29: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/29.jpg)
Plaque Rupture with ThrombosisPlaque Rupture with Thrombosis
Thrombus Fibrous cap
1 mmLipid core
Illustration courtesy of Frederick J. Schoen, M.D., Ph.D.
![Page 30: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/30.jpg)
Thrombosis of a Disrupted Atheroma, the Thrombosis of a Disrupted Atheroma, the Cause of Most Acute Coronary Cause of Most Acute Coronary Syndromes, Results from:Syndromes, Results from:
Weakening of the fibrous cap
Thrombogenicity Thrombogenicity of the lipid coreof the lipid core
Illustration courtesy of Michael J. Davies, M.D.
![Page 31: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/31.jpg)
CD40 and Tissue Factor in AtheromaCD40 and Tissue Factor in Atheroma
CD40
Mach F et al. Circulation 1997;96:396-399.
Tissue Factor
![Page 32: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/32.jpg)
CD40 Ligation Induces Tissue Factor CD40 Ligation Induces Tissue Factor Expression in Human Monocyte-Derived Expression in Human Monocyte-Derived MacrophagesMacrophages
Log Fluorescence
Cell
Nu
mb
ers
160
120
80
40
0
160
120
80
40
0100 101 102 103 100 101 102 103
rCD40L/-CD40L
rCD40L
T cell/membranes/-CD40L
T cell/membranes
Mach F et al. Circulation 1997;96:396-399.
![Page 33: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/33.jpg)
CD40 ligand on activated platelets CD40 ligand on activated platelets
triggers an inflammatory reaction of triggers an inflammatory reaction of
endothelial cellsendothelial cells
Henn V et al. Nature 1998;391:591-594.
![Page 34: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/34.jpg)
Inflammation Can Promote ThrombosisInflammation Can Promote Thrombosis
PlateletPlatelet
TissueTissueFactorFactor
FibrinogenFibrinogen
Via gp llb/lllaVia gp llb/llla
FibrinFibrinCD40LCD40LPlatelet-Platelet-
FibrinFibrinThrombusThrombus
FibrinopeptidesFibrinopeptides
PlateletPlatelet
![Page 35: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/35.jpg)
Inflammation Participates in All Phases of Inflammation Participates in All Phases of Atherothrombotic DiseaseAtherothrombotic Disease
Lesion initiation
Lesion progression
Thrombotic complications
![Page 36: Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall](https://reader034.vdocuments.net/reader034/viewer/2022051821/5697bfe91a28abf838cb6ed7/html5/thumbnails/36.jpg)
Slide Source:Lipids Onlinewww.lipidsonline.org
Thanks