L.19 Artherosclerosis Flashcards
Describe the structure of normal tunica intima
Endothelial cells w tight junct control what goes through the vessel wall.
On top of basement membrane with CT and proteins which trap growth factors and have function in signalling. Mobile myointimal cells throughout.
Describe the structure of normal tunica media
Smooth muscle cells regulate flow by contraction, stabilise endothelial cells by secreting ECM and activating growth factors.
Elastic lamina layers: assist continuous flow by elastic recoil
Collagen: resists tension
Describe the normal tunica adventitia
Made of CT: lymphatic, nerves, leukocyte, fibroblasts, vasa vasorum *diffusion distance too great
What is artherosclerosis: an example of chronic inflammation
A disease that affects the tunica intima of large/ medium size arteries where focal deposits of fibrous tissues (fibrous cap) and lipids with a necrotic centre called plaques form and harden arteries.
What are the main risks for artherosclerosis
- High levels of lipids in the blood- LDL, cholesterol
- Cigarette smoking toxins injuring endothelium
- Hypertension injuring endothelium
- Diabetes mellitus
- Advancing age: largely asymptomatic for decades.
What are the protective factors
- High levels of high density lipoproteins
- Moderate alcohol consumption (uncertain)
- Cardiovascular fitness
What is the first stage of artherosclerosis formation: initiation
Endothelial injury caused by haemodynamic force, chemical insult, cytokines.
- Results in Altered permeability which allows lipids to infiltrate if high in the bloodstream.
- Adhesion of leukocytes: acute inflammation because of increased chemokine expression: selectins, integrins, addressins.
- Activation of thrombosis
What happens after initiation of athersclerois (2nd step)
- Leukocyte migration into the developing plaque:
- Monocytes enter the atherosclerotic lesion after adhering to endothelial cells and then differentiate into macrophages
- They ingest large amounts of oxidised lipoproteins (from enzymes from the surrounding cells) which turns them into Foam cells
- When they die (necrosis) their contents spill into the extracellular space leading to cholesterol crystals and clefts of precipitated fats.
- Mast cells in plaque degrade protective HDL and promote smooth muscle and leukocyte migration into plaque
Is there a genetic component to predisposition to artherosclerosis
As we age we accumulate somatic mutation in some of our haemopoetic stem cells which give a mild growth advantage which will drive artherosclerosis quicker. -Clonal haematopoiesis of indeterminate potential.
What is the role of smooth muscle cells in artherogenesis (step 3 )
- GF from macrophages, platelets and endothelial cells activate vascular smooth muscle cells
- They proliferate and migrate into the tunica intima from the media into the plaque just under the endothelial cells. They can stabilise the plaque by producing CT fibres. (not really contractile anymore)
- Accelerated by the breaks in the internal elastic lamina.
- Activated smooth muscle cells produce cytokines and chemokines that activate leukocytes, take up lipids through specialised receptors.
What is the role of lipoproteins in artherogenesis (step 4)
Lipoproteins become oxidised in plaques by enzymes. They can chemoattract monocytes, stimulate other cell types to release cytokines and GFs. Cause dysfunction and apoptosis in smooth muscle cells, macrophages and endothelial cells
What are the complications of artherosclerosis
Artheroma are often silen until they suddenly cause symptoms: advanced vulneral plaque.
This can be due to mural thrombosis, embolisation and wall weakening -> -Aneurysm and rupture
+plaque erosion, rupture, haemorrhage
-Occlusion by thrombus
or
progressive plaque growth: critical stenosis.
Therefore myocardial infarction, periph vascular disease and stroke.
