1b Vascular Endothelium Flashcards
What are blood vessels lined by?
Endothelial cells
What are the three layers of blood vessels, except capillaries and venules?
Tunica Adventitia - vasa vasorum and nerves
Tunica Media - external elastic membrane and smooth muscle
Tunica Intima - endothelium - lamina propria
What is contained within the lamina propria?
Smooth muscle and connective tissue
What is the site of exchange of nutrients and oxygen between blood and tissues?
Capillaries
What 2 features are capillaries and venules supported by?
Mural cells (pericytes) - regulate blood vessel diameter
Basement membrane - filter for substances
What properties do endothelial cells have?
Organotypic - tissue specific properties with unique gene/protein expression proteins
Why does microvasculature look different in different organs?
Endothelial cells are heterogenic
Endothelial cells and microvasculature have organotypic (tissue-specific) properties and expression profiles
What is the surface area thickness diameter and weight of the endothelium?’
Surface area > 1000m^2
Weight > 100g
1-2 micrometer thick
10-20 micrometer in diameter
What is contact inhibition?
Endothelial cells forming cell-cell junctions signal to one another when they make contact to inhibit each other’s further growth
What is the proliferation rate of endothelial cells?
Low proliferation rates, unless new vessels are required = angiogenesis
What are the 6 main functions of blood vessels and tissues that are controlled by endothelium?
Permeability
Angiogenesis
Vascular Tone
Inflammation
Tissue homeostasis and regeneration
Haemostasis and Thrombosis
At resting state, what does the endothelium induce with respect to inflammation, thrombosis and proliferation?
The endothelium is:
Anti-inflammatory
Anti-thrombotic
Anti-proliferative
When activated, how does the endothelium change to suit a pro-inflammatory environment?
The endothelium is:
Pro-inflammatory
Pro-thrombotic
Pro-angiogenic
What different environmental / physiological factors can lead to an activated endothelium?
Inflammation
Mechanical stress
Ox LDL
High blood pressure
Smoking
Viruses
High glucose
What is angiogenesis?
The formation of new vessels by sprouting from existing vessels
What is the main trigger for angiogenesis?
Hypoxia
What three physiological events is angiogenesis needed for?
Development
Menstrual Cycle
Wound Healing
What are pathological causes for angiogenesis?
Cancer
Retinopathies
Atherosclerosis
What 4 things can an activated endothelium lead to, as implicated in the pathophysiology of atherosclerosis?
1) Thrombosis
2) Leukocyte recruitment
3) Senescence - cell stops dividing but does not die
4) Permeability
How do tumours stimulate angiogenesis?
Secretes angiogenic factors that stimulate migration, proliferation and neovessel formation by endothelial cells in adjacent established vessels
What is the angiogenic switch?
When the amount of angiogenic factors released > the amount of anti-angiogenic, so new vessel formation occurs which then supplies the tumour
Describe the shape of tumour blood vessels?
Irregularly shapes, dilated, tortuous
How are tumour blood vessels organised?
Not into definitive venules, arterioles and capillaries
What are two characteristics of tumour blood vessels?
leaky and heamorrhagic = due to overproduction of VEGF
What is thromboinflammation?
Loss of anti-thrombic and anti-inflammation functions of endothelial cells causing thrombosis with associated inflammation
How does VWF impact angiogenesis?
Controls blood vessel formation and integrity partly by regulating growth factor signalling
In response to injury, what is the pathogenesis of atherosclerosis??
1 - Endothelial Dysfunction in Atherosclerosis
= Endothelial permeability ↑
= Leukocyte migration ↑ into the subendothelial space
= Leukocyte adhesion = ↑
2 - Fatty Streak Formation in Atherosclerosis
= fatty-Streak Formation
- Formation of an advanced lesion
= Macrohpgae accumulation
= Formation of necrotic core
= Angiogenesis
Recruitment of blood leukocytes into tissues normally takes place during inflammation, where do leukocytes adhere to?
Adhere to endothelium of post-capillary venules and transmigrate into tissues
In atherosclerosis, where do leukocytes adhere to and what happens after it does this?
Activated endothelium of large arteries
Gets stuck in the subendothelial space
What is a post-capillary venules?
Structure similar to capillaries but more pericytes
What happens to monocytes when they migrate to the sub-endothelial space?
Differentiate into macrophages and become foam cells
What is the endothelium important in regulating?
The flux of fluids and molecules from blood to tissues and vice verca
What is the consequence of increased vascular permeability?
Results in leakage of plasma proteins through the junctions into the sub-endothelial space
How does the increased permeability of the endothelium lead to atherosclerosis?
Lipoproteins enter subendothelium through weaknesses in the endothelium which then bind to proteoglycans and the lipoproteins are oxidated in the environment of the subendothelium
Macrophages come and agglutinate the proteoglycan-lipoprotein complexes which leads it to become a foam cell
Where do atherosclerotic plaques preferentially occur?
At bifurcations and curvatures of the vascular tree
Why do atherosclerotic plaque prefer to occur at bifurcations of blood vessels?
The flow patterns and haemodynamics forces are not uniform in the vascular system
What is the wall shear stress?
Force per unit area exerted by the wall on the fluid in a direction on the local tangent plane
In straight parts of the arterial tree what is the wall shear stress described as?
high and directional
In branches and curvatures, how is blood flow disturbed and what is the resultant effect on wall shear stress?
Blood flow is disturbed with non-uniform and irregular distribution of low wall shear stress
What four things does laminar blood flow promote?
Anti-thrombotic, anti-inflammatory factors
Endothelial survival
Inhibition of SMC proliferation
Nitric Oxide (NO) production
What does disturbed blood flow promote?
Thrombosis
Inflammation (leukocyte adhesion)
Loss of Nitric Oxide production
Endothelial apoptosis
SMC proliferation
What are 6 functions of Nitric Oxide that make it essential for the health of the cardiovascular system?
- Vasodilation
- reduce platelet activation
- Inhibits monocyte adhesion
- Inhibits proliferation of SMC in the vessel wall
- Reduces release of superoxide radicals
- Reduces oxidation of LDL cholesterol (major constituent of plaque)
What does angiogenesis promote?
Plaque growth
Therapuetic angiogenesis prevents damage post-ischemia
Is coagulopathy associated with high or low levels of D-Dimers and Fibrinogen?
high
In severe Covid-19, what could be used as a marker for endothelial injury?
Levels of circulating endothelial cells
High D-Dimer levels would be a marker for disease progression
-
How are endothelial cells involved in the propagation of COVID-19 infection?
SARS-CoV2 Infection = Cytokine storm = endothelial activation = procoagulant switch
How would you decrease the increased circulating endothelial cells in COVID-19 patients due to endothelial damage?
Give anticoagulants
What does a higher than normal D-Dimer level mean?
That you have significant blood coagulation
High levels of troponin?
An issue with the heart as it releases troponin into the blood following an injury such as a myocardial infarction
What is the main 2 mechanisms by which COVID can cause activation and damage to the endothelium?
Cytokine storm secondary to SARS-CoV2 infection causes endothelial damage
SARS-CoV2 enters endothelial cells and causes direct damage
Is ACE2 expressed on epithelial or endothelial cells?
Epithelial
Does SARS-CoV2 replicate in endothelial cells?
no
What are the factors which the microvascular endothelial cells produce?
Angiocrine factors
What are angiocrine factors?
Angiocrine factors are factors which can promote the tissue repair of specific tissues - vital for the maintenance of tissue homeostasis and regeneration
