18. Vascular Endothelium Flashcards
What is the atherosclerosis timeline?
1) Foam cells
2) Fatty streak
3) Intermediate lesion
4) Atheroma
5) Fibrous plaque
6) Complicated lesion/rupture
What are the 3 layers of the blood vessels?
- Tunica intima - endothelium
- Tunica media - VSMCs
- Tunic adventitia - Vasa Vasorum (small blood vessels), Nerves
What is contact inhibition?
Regulatory mechanism in endothelial cells that makes sure they form a monolayer
What 4 main things do the functions of endothelial cells involve?
- Inflammation
- Vascular Tone and Permeability
- Angiogenesis
- Thrombosis and Haemostasis
What state do resting endothelial cells maintain compared to someone who has cut themselves?
(in terms of inflammation, thrombosis and angiogenesis)
Normal
• Anti-inflammatory
• Anti-thrombotic
• Anti-angiogenic
Cut
• Pro-inflammatory
• Pro-thrombotic
• Pro-angiogenic
In which part of the endothelium do leukocytes normally adhere to?
Post-capillary venules
In which part of the endothelium do leukocytes adhere to during atherosclerosis?
Activated endothelium of large arteries
Why does the activated endothelium attract leukocytes?
- Normally the selectins and integrins on leukocytes are turned off
- Some are turned on but don’t have complementary receptors on the endothelium
- Inflammation => activated endothelium => starts to express ligands
- Selectins on leukocyte weakly interacts with the endothelium
- Integrin high affinity state - strong binding
- Adhesion and transmigration
What is V-cadherin?
A protein present at endothelial junctions
How do endothelial cell membranes bind to each other?
- Homophilic attraction
- Binding membrane creates a zipper
- Junctions can unzip allowing substances to pass
What happens to babies born with integrin mutations?
- Live for around 3 months
- Unable to deal with infection
- Mutations in molecules are not compatible with life
What surrounds the endothelial cells in the capillary and post-capillary venule?
- Basement membrane
- Pericapillary cells (perycites)
- More pericytes in the post-capillary venule
How do leukocytes pass through the basement membrane?
- Enzymes used to break it down in its path, allowing them to pass through
- Thick layer in coronary artery or aorta stops it from passing => atherosclerosis
What is a positive protective signal?
- Laminar flow sensed by the endothelium
* Production of protective molecules e.g. NO and anticoagulants, is triggered
What does turbulent flow promote?
- Coagulation
- Leukocyte adhesion
- VSMC proliferation
- Endothelial apoptosis
What are epigenetics?
Functionally relevant, inheritable changes to the genome that do not involve a change in the nucleotide sequence, which affect gene expresison
How do epigenetics play a role in the affect of flow on atherogenesis?
• Laminar flow
- downregulates the expression of DNA methyltransferases (DNMTs)
- Promoter of antiatherogenic genes remain demethylated
- Expression enabled => anti-atherogenesis
• Turbulent flow
- upregulates the expression of DNA methyltransferases
- Hypermethylation of promoter of antiatherogenic genes
- Expression repressed => pro-atherogenesis
What is angiogenesis?
Formation of new blood vessels by sprouting from pre-existing vessels
What triggers angiogenesis?
- Tissue becomes hypoxic
- Releases chemicals which activate existing blood vessels
- Change in the cells triggered
- Cells that become a ‘tip cell’ control the formation of a new blood vessel
- Stabilised blood vessel forms
What is The Janus Paradox?
Negative side of angiogenesis
• Advanced plaque
• Necrotic debris => hypoxia => angiogenesis from the Vasa Vasorum
• Vasa Vasorum vessels are fragile - more leukocytes will come
Positive side of angiogenesis
• Therapeutic angiogenesis
• Useful when Acute Myocardial Infarction leads to fibrotic tissue where the ischaemia had an impact
• If done quickly - myocardium could be reoxygenated preventing tissue damage and heart failure
What is senescence?
- Growth arrest that halts the proliferation of ageing or damaged cells
- Prevents damaged cells from taking over (mechanism against cancer)
What is a negative affect of senescent cells?
- Senescent cells can develop a proinflammatory phenotype
- Senescence can be induced by cardiovascular risk factors
- Found in atherosclerotic lesions
What does red wine contain and what effect does this have?
- Resveratrol
- Anti-inflammatory properties on the endothelium
- Hormetic action - beneficial at lower doses, cytotoxic at higher doses
