Vascular Endothelium II Flashcards
What is atherosclerosis?
build up of fibrous and fatty material inside arteries underlying CVD
chronic inflammatory disease
Response to injury model?
1 - endothelial dysfunction
2 - fatty streak formation
3 - advanced complicated lesion forms
Describe step 1 of endothelial dysfunction?
- receive chronic stimuli (high BP - high cholesterol) that lead to dysfunction
- increase endothelial permeability (NO, ETs, Ang II, prostacyclin)
- lipid moves through also
- increase leukocyte adhesion and migration under endothelium
Describe step 2 of fatty streak formation?
foam cells form
platelets adherence and aggregation
smooth muscle migration
leukocyte adherence and entry
Describe step 3 of advanced complicated lesion forming?
macrophages accumulate necrotic core forms senescence angiogenesis fibrous cap forms
What are the 3 layers of a blood vessel?
tunica adventitia
- vasa vasorum, nerves
(network of small blood vessels that supply walls of larger blood vessels)
tunica media - smooth muscle cells
tunica intima - endothelium (single layer of cells)
How do endothelial cells ensure they form a monolayer?
contact inhibition
cells are stable, new ones only form in angiogenesis and healing
What must endothelial cells maintain a balance between?
pro and anti inflammatory
healthy cells: antithrombotic/inflammatory/proliferative
unhealthy cells: reverse
in atherosclerosis this is chronic due to chronic stimuli that disrupt balance
What are processes that lead to atherosclerosis?
thrombosis
senescence
permeability
leukocyte recruitment
chronic stimuli: smoking, high BP, viruses, inflammation, mechanical stress, pro inflammatory cytokines (IL-1, TNF), disturbed blood flow
What normally happens to leukocytes and what happens during atherosclerosis?
NORMAL - during inflammation they adhere to endothelium of post capillary venule and transmigrate into tissues
ATHERO - adhere to endothelium of large arteries
stuck in sub-endothelial space due to thick arterial wall, or via post capillary venules of developing lesions
- activated endothelium allows lipoproteins to move into sub-endothelial layer
monocytes also migrate across and differentiate to macrophages - Lipoproteins are oxidised by oxidative environment of macrophage secretions
- Macrophages phagocytose lipoproteins and form foam cells
- fatty streaks form as leukocytes accumulate lipids
Describe extravasation/diapedesis
1 - molecules of leukocyte are in low affinity state
2 - chronic stimuli activate endothelium to express ligands for leukocytes so integrins weakly interact with endothelium selectins –> ROLLING
3 - internal signals switch integrins to high affinity state on leukocyte
4 - leukocytes bind strongly, adhere and transmigrate
How do leukocytes transmigrate through endothelium?
squeeze through endothelial junctions
V-CADHERIN is at all junctions
at junction both endothelial cell surface molecules bind homophilically to move through layer
How is diapedesis shown?
intra-vital microscopy
What determines vascular permeability and what is the consequence of increased permeability?
determined by endothelial cell-cell junctions
increase permeability causes increased leakage of plasma proteins into the sub-endothelial space through junctions
–> oedema
–> if lipids leak through can cause early plaque formation
How does blood flow influence endothelium?
atherosclerosis forms more commonly at bifurcations due to turbulent flow
laminar flow promotes increases shear stress and reduced risk of atherosclerosis, NO production, inhibition of coagulation, endothelial cell survival
turbulent flow promotes chronic endothelial cell activation, coagulation, inflammation, leukocyte adhesion, endothelial cell apoptosis
