Vascular Endothelium Flashcards
Blood vessels are lined by which cells?
Endothelial cells
What are the three layers of blood vessels (apart from capillaries and venules)?
What percentage of endothelial cells reside within the microvasculature?
98%
Describe the structure of capillaries and venules
Formed only by endothelium
Supported by some mural cells (pericytes) and a basement membrane
Where does exchange of nutrients and oxygen between blood and tissues occur?
Capillaries
What findings suggest that microvascular endothelium promotes tissue homeostasis?
Damage to the endothelium can cause organ dysfunction
Are blood vessels just a distribution system?
No
Microvascular endothelium are the source of what factors and what are these factors required for?
Source of angiocrine factors
Factors are required for maintenance of tissue homeostasis and organ regeneration
Dysfunctional endothelium contributes to which conditions?
Contributes to disease more than any other organ:
Ischaemia
Chronic inflammatory diseases
Cancer
Diabetes
Are all blood vessels the same?
No, there is vascular and endothelial heterogeneity
Endothelial cells and microvasculature have organotypic (tissue-specific) properties and expression profiles
Describe the structure of endothelial cells
Very flat
1-2 micrometers thick and 10-20 micrometers in diameter
How do endothelial cells grow to from the endothelium?
Endothelial cells come together to form cell-cell junctions
Establishment of the junction (contains a lot of complex molecular structures) results in growth inhibition - cells stop growing
This is known as contact inhibition
Describe the proliferation rate of endothelial cells
Low
Only proliferate during angiogenesis, where new vessels are required
What is the function of endothelial cells?
Regulate essential functions of blood vessels:
Vascular tone
Angiogenesis
Permeability
Inflammation
Homeostasis and thrombosis
At rest, what kind of factors are produced by the vascular endothelium?
Anti-inflammatory
Anti-thrombotic
Anti-proliferative
When activated, what kind of factors are produced by the vascular endothelium?
Pro-inflammatory
Pro-thrombotic
Pro-angiogenic
What factors may contribute to chronic activation of the endothelium?
Smoking
Viruses
Mechanical stress
Inflammation
High BP
OxLDL
High glucose
Over time, what does chronic activation of the endothelium promote and what do these factors lead to?
Thrombosis
Leukocyte recruitment
Increased permeability
Ageing of endothelial cells (senescence)
Lead to atherosclerosis
What stimuli and risk factors are implicated in endothelial cell dysfunction in atherogenesis?
What are the four mechanisms of endothelial dysfunction in the pathogenesis of atherosclerosis?
Leukocyte recruitment
Permeability
Shear stress
Angiogenesis
Describe the leukocyte adhesion cascade
In physiology, when does leukocyte recruitment occur and where?
Takes places during inflammation
Leukocytes adhere to endothelium of post-capillary venules and transmigrate into tissues
What is the difference between a capillary and a post-capillary venule?
Structure similar but venules have more pericytes
How is leukocyte recruitment different in atherosclerosis?
Leukocytes adhere to activated endothelium of large arteries and get struck in subendothlial space
Monocytes migrate into subendothelial space -> differentiate into macrophages -> become foam cells (following phagocytosis)
How does vascular permeability contribute to atherogenesis?
Increased permeability results in leakage of plasma proteins through junctions into the subendothelial space
Lipoprotein trapping (by proteoglycans, ECM) and oxidation
Macrophages phagocytose material -> formation of foam cells
Where does atherosclerosis typically occur and why?
Branch points - bifurcations and curvatures of the vascular tree
Flow pattern and haemodynamic forces are not uniform in the vascular system - turbulent vs laminar flow
Describe blood flow and shear stress in ‘straight’ parts of the arterial tree
Laminar blood flow
Wall shear stress is high and directional
Describe blood flow and shear stress in the branches and curvatures of the arterial tree. What can this cause?
Disturbed/turbulent blood flow
Non-uniform/irregular distribution of low wall shear stress
Can cause chronic endothelial activation
Describe the protective effect of laminar blood flow on the vascular endothelium?
Promotes
-Antithrombotic and anti-inflammatory factors
-Endothelial survival
-Inhibition of smooth muscle cell proliferation
-Nitric oxide production
Disturbed blood flow promotes the exact opposite
Outline the protective effects of NO on the vascular endothelium
Essential for health of CVS
- Dilates blood vessels
- Reduces platelet activation
- Inhibits monocyte adhesions
- Reduces proliferation of SMC in vessel wall
- Reduces release of superoxide radicals
- Reduces oxidation of LDL cholesterol (major plaque component)
Define angiogenesis
Formation of new vessels by sprouting from existing vessels
Angiogenesis is essential for what physiological processes?
Embryonic development
Menstrual cycle
Wound healing
Describe the JANUS paradox of angiogenesis and cardiovascular disease
Angiogenesis promotes plaque growth in advanced atherosclerosis
However, therapeutic angiogenesis prevents damage post-ischaemia (e.g. MI)
Describe the pathogenesis of atherosclerosis using the response to injury model
- Endothelial dysfunction
- Endothlial permeability
- Leukocyte migration
- Leukocyte adhesion - Fatty-streak formation
- Foam-cell formation - Formation of an advanced, complicated lesion
- Macrophage accumulation
- Formation of a necrotic core
- Angiogenesis
What processes promote early development of atherosclerotic plaques?
Endothelial activation
Leukocyte adhesion
Increased permeability to lipids
What is thromboinflammation caused by and which recent disease is it thought to be associated with?
Loss of normal antithrombotic and anti-inflammatory functions of endothelial cells - leads to thrombosis and associated inflammation
Occurs in many disorders - thought to occur in COVID 19
Describe two possible mechanism of endothelial activation and damage in COVID-19
- COVID Infection -> cytokine storm -> endothelial activation -> procoagulant switch
- Virus enters endothelial cells and causes direct damage (ACE2 expressed in EC?)
