Atherogenesis

Question 1

What are atherogenic plaques composed of?

Answer 1

Cells (smooth muscle cells, macrophages (foam cells), T cells)
Matrix components (collagen, proteoglycans, elastic fibres)
Intracellular and extracellular lipid (cholesterol and cholesterol esters)

Question 2

Describe the normal role of the endothelium

Answer 2

Normal endothelium has anti-coagulant and anti-adhesion properties

Question 3

Describe early dysfunction of the endothelium in the context of atherogenesis

Answer 3

Increased permeability to lipoproteins
Allows inflammatory cells into vascular wall
Loss of cell-repellent quality

Question 4

How are monocytes attracted to developing plaques?

Answer 4

Attracted to developing plaques by MCP-1/CCL2

Question 5

What happens to the monocytes when they are attracted to the developing plaques?

Answer 5

Transform into macrophages under influence of cytokines (IFN-γ, TNF-α, GM-CSF, M-CSF) secreted by endothelium and vascular smooth muscle cells (VSMC)

Generate Reactive Oxygen Species (ROS) which can oxidise LDL in intima

Produce pro-inflammatory cytokines

Express scavenger receptors

Question 6

Which type of lipid is the most atherogenic?

Answer 6

LDL

Question 7

What is the problem with oxidised LDL?

Answer 7

Stimulates expression of VCAM-1 and MCP-1; directs macrophages to sites of lesions

Oxidised B-100 binds to scavenger receptors on macrophages and is phagocytosed

No feedback regulation via cholesterol concentration

Generation of foam cells (visible in arterial walls as fatty streaks)

Question 8

What happens when you upregulate VCAM-1?

Answer 8

Increased migration of monocytes from blood into the artery

Question 9

What does non-oxidised LDL bind to?

Answer 9

LDL receptors

Question 10

What are foam cells?

Answer 10

Macrophages filled with lipids

Question 11

What do foamy macrophages do?

Answer 11

Drive the inflammatory process

Question 12

Describe how endothelial cells and macrophages affect the vascular smooth muscle cells

Answer 12

Endothelial cells and macrophages secrete: PDGF and TGF-β

Effect on VSMCs: proliferation and migration into the intima

Question 13

What do the activated VSMCs do>

Answer 13

Activated VSMCs also synthesise ECM (collagen in particular) which deposits in the plaque

Question 14

Summarise the process of atherogenesis

Answer 14

Hyperlipidemia, hypertension, smoking, high LDL, toxins and haemodynamics cause endothelial injury/dysfunction
Monocytes recruited from the blood and enter the artery wall
Lots of LDL in the macrophages forming foam cells
Release of pro-inflammatory cytokines
Foam cells form fatty streak.
Growth factors from foam cells cause migration and proliferation disrupting the structure of the artery wall
ECM synthesis causing a fibrous plaque to form

Question 15

Describe the differences between a smooth plaque and a ruptured plaque

Answer 15

Stable plaques have a thick fibrous cap whereas ruptured plaques have a thin fibrous cap
Stable plaques have a high VSMC content whereas ruptured plaques have a low VSMC content
Stable plaques have a small lipid pool and low number of inflammatory cells whereas the opposite is present in ruptured plques

Question 16

Describe the lipid oxidation hypothesis of atherogenesis

Answer 16

LDL enters vascular wall and become oxidised
Oxidised LDL phagocytosed by macrophages
Generation of foam cells
Recruitment of macrophages
Generation of plaques

Question 17

Describe the response to injury hypothesis

Answer 17

Endothelial dysfunction
Accumulation of lipoproteins 
Monocyte and platelet adhesion
Smooth muscle proliferation 
Lipid accumulation

Question 18

List the risk factors for endothelial injury

Answer 18

raised LDL
‘toxins’ eg cigarette smoke
hypertension
haemodynamic stress

Question 19

What does endothelial injury cause?

Answer 19

platelet adhesion, PDGF release, VSMC proliferation and migration
insudation of lipid, LDL oxidation, uptake of lipid by VSMC and macrophages
migration of monocytes into intima

Question 20

What do stimulated VSMC and foam cells DO?

Answer 20

Stimulated VSMC produce matrix material

Foam cells secrete cytokines causing
further VSMC stimulation
recruitment of other inflammatory cells

Question 21

Early dysfunction of the endothelium is… rather then …

Answer 21

Functional

Structural