Vascular Disease: Atherosclerosis Flashcards
Causes and clinical symptoms of Arterial blockage
Caused by formation of lesions and plaques building up in the arteries
Clinical symptoms:
- heart attack, heart failure, stroke, pulmonary blockage, peripheral arterial disease, coronary heart disease
Steps of Atherosclerosis
1) normal
2) fatty streak
3) fibrous plaque (largely consisting of immune cells)
4) complicated lesion (cellular debris, cholesterol, foam cells, immune cells…)
5) Destabilisation/rupture causing clot
Arterial blood clotting (‘plugging up’ the artery)
Sudden rupturing of an atherosclerotic plaque causes a thrombus which can cause heart attack/stroke (if in brain)
- plaque comes as a result of vascular dysfunction
- platelets in thrombus aim to ‘plug up’ the ruptured endothelial cell wall/plaque but also plug up the entire artery
How blood-lipid levels are linked to atherosclerosis (AS)
lipid particles = phospholipid monolayer (apo-lipoproteins) + central core of cholesteryl esters & non-polar lipids
- cholesterol levels = proportional to incidence of AS
- blood cholesterol >4.8-5.1 mmol/L = unhealthy (high levels = heart attacks)
Cholesterol structure and uses
A 27-carbon amphipathic molecule
- 4 ring steroid nucleus
- OH group on C3
- Amphipathic: polar OH, hydrophobic tail
Uses (found largely in higher eukaryotes):
- biological membranes
- Vit D synthesis, Ca homeostasis
- steroid hormone biosynthesis
- bile synthesis
LDL levels linked to AS
Low Density Lipoproteins = key cholesterol carriers circulating in blood stream
In high pressure arteries, LDL can get pushed into artery vessel walls & accumulate (leading to AS)
Defects in LDL receptors can increase risk of AS:
- LDLRs normally remove LDL from blood
- defective LDLRs = increased blood-LDL concentrations
- Increased LDL concentration means more likely to enter arterial walls
How LDL accumulation in arterial walls leads to AS
1) ROS modify LDL into oxLDL in the artery wall
2) oxLDL promotes endothelial cells to express leukocyte adhesion molecules (VCAM1), recruiting monocytes and T cells
3) Monocytes differentiate into macrophages (due to MCSF) that engulf/uptake oxLDL
4) excessive oxLDL uptake turns macrophage into Foam cells which die and accumulate
5) Foam cells promote production of more pro-inflammatory signal molecules (TL9 binding promotes IFNg secretion + IL2,6 and 1.
Normal LDLR-LDL trafficking
LDLR-LDL complex gets endocytosed and is delivered to early endosomes where LDLR-LDL uncouple
- LDLR recycles to cell surface, LDL is transported to late endosomes/lysosomes where it’s broken down into cholesterol
Self-regulation: cholesterol regulates transcription of LDLR gene
How cholesterol regulates transcription of LDLR gene
Cholesterol sensing proteins (SREBPs) located in the ER and Golgi respond to free cholesterol in the cell
- the proteins are cleaved and enter the nucleus to act as transcriptional coregulators (e.g. inhibiting LDLR synthesis if high cholesterol levels detected)
Atherosclerotic plaque initiation:
LDL modification and leukocyte differentiation
LDL is modified into mLDL & oxLDL
- modified LDLs are recognised by vascular cells to trigger pro-inflammatory responses, recruiting monocytes
Leukocytes/monocytes enter arterial wall
- macrophage differentiation –> foam cell formation
Monocyte recruitment
Macrophage becoming foam cells
Monocytes circulating the blood stream enter the Intima of blood vessel via endothelial lining (Trans-Endothelial Migration, TEM)
- Monocytes detect macrophage-activating factors and differentiate
Macrophage bind & engulf oxLDL & mLDL
- become fat-rich and begin to die
- fat-engorged macrophage differentiate into foam cells (very large cells)
- foam cells dies and form core of lesion/plaque
Vascular Smooth Muscle Cells (VSMCs)
important in vascular constriction and relaxation (blood pressure)
contribute to plaque formation through cellular apoptosis and remodelling around damaged areas of artery
Platelets regulate blood clot (thrombus) formation
Platelets, produced by magakaryocytes, interact with vasculature via cell surface receptors
- fibrinongen and VWF binding is critical for platelet aggregation/clot formation
- leukocytes and endothelial cells also interact with platelets
How inflammation alters the endothelial-leukocyte adhesion dynamics
Increased inflammation (by infection too) increases endothelial-leukocyte adhesion meaning more monocytes and an increased chance of AS
Trans-Epithelial Migration (TEM)
a.k.a. Diapedesis: Leukocytes interacting with endothelium to enter tissues nearby
1) Tethering and rolling
2) Activation
3) Firm adhesion
4) Transmigration
- leukocyte squeezes between 2 endothelial cells
- EC-EC connections are temporarily disrupted
