Cardiovascular Systems 9 - Vascular Endothelium 2 Flashcards
Describe the basic structure of blood vessels.
- There are three layers
- The top layer is the tunica adventitia (vasavasorum, nerves)
- Tunica media below (smooth muscle cells)
- Tunica intima is the inner layer, containing the endothelium
List the stimuli of endothelial cell dysfunction, resulting in atherogenesis.
- Oxidative stress
- Proinflammatory cytokines
- Infectious agents
- Environmental toxins
- Disturbed blood flow
- Hypercholesterolaemia
- Diabetes mellits
- Hypertension
Describe the process of leukocyte recruitment in atherosclerosis.
- Leukocytes adhere to activated endothelium of large arteries and get trapped in the sub-endothelial space
- This occurs as activation of the endothelium stimulates the expression of receptors
- Leukocytes also enter at post-capillary venules
- Monocytes migrate into the sub-endothelial space forming macrophages
What is the difference between the capillary and the post-capillary venules?
- Capillaries consist of endothelial cells surrounded by a basement membrane and pericapillary cells (pericytes)
- Post-capillary venules have a similar structure but with more pericytes
Describe the process of lipoprotein trapping in atherosclerosis formation
- Activated endothelial cells have high permeability and allow the lipoproteins to diffuse across the endothelium
- They encounter proteoglycans and are oxidated
- Macrophages then engulf all of the lipoproteins and form a foam cell
- Forms fatty streaks
Why does aterosclerosis happen at branch points?
- There is a difference in blood flow
- Laminar flow occurs in vessels with a constant diameter, while turbulent flow occurs at branch points due to bends and narrowings.
- Turbulent flow promotes coagulation, leukocyte adhesion, and reduced NO production.
List the positive effects of nitric oxide on the vascular endothelium.
- Dilates blood vessels
- Reduces LDL oxidation
- Reduces platelet activation
- Inhibits monocyte adhesion
- Reduces proliferation of smooth muscle cells in atherosclerosis
- Reduces release of superoxide radicals
What transcription factor is present in the atherosclerosis susceptible region?
NF kappa B (activates cytokine production, and is proinflammatory)
List the three key epigenetic mechanisms.
- DNA methylation
- Histone modification
- miRNA
Why is the study of epigenetics important in atherosclerosis?
As epigenetics could be targeted by drugs
How does stable flow prevent atherosclerosis?
- Downregulates expression of DNA methyltransferases
- This ensures antiatherogenic genes, such as KIf4 and HoxA5 remain demethylated, enabling their expression
How does disturbed flow increase atherosclerosis?
- Increases expression of DNA methyltransferases
- Results in hypermethylation of antiatherogenic genes, like KIf4 and HoxA5
- This reduces their expression
What is angiogenesis?
The formation of new vessels by sprouting from existing vessels
What processes are angiogenesis essential for?
- Embryonic development
- Menstrual cycle
- Wound healing
What are the pros and cons of angiogenesis?
- It prevents damage after ischaemia
- However, it promotes growth of plaque
What is cellular senescence?
Growth arrest that halts the proliferation of ageing and/or damaged cells.
What are the pros and cons of senescence?
- Senescence prevents the transmission of damage to daughter cells
- Senescent cells are pro-inflammatory and contribute to many diseases
- Senescent endothelial cells are found in atherosclerotic lesions
Why may senescent cells contribute to atherosclerosis?
As they have a proinflammatory and prothrombotic phenotype.
Describe the stages of pathogenesis of atherosclerosis.
- Lipoprotein permeability increases, and foam cells form
- These fatty streaks then progress to advanced lesions, with a fibrous cap to separate the lesion from the lumen.
- The fibrous cap contains leukocytes, lipid and deris, which form a necrotic core.
- Senescence also occurs.
What are the benefits of resveratol?
- Promotes endothelial protective pathways, such as eNOS
- Reduces cell senescence
- Prevents pro-inflammatory changes
Where is resveratol used?
- Used by the general public for its health benefits
- Clinical benefits not demonstrated
What is the risk of resveratol use?
It is hormetic (effective at low doses, but cytotoxic at high doses)
What can be used to maintain vascular homeostasis?
- Diet and exercise
- Statins (decreases LDL)
- New therapies
In which vessels does leukocyte transmigration occur?
Post capillary venules
What promotes early development of atherosclerotic plaques?
- Endothelial activation
- Permeability
- Leukocyte adhesion
