Cardio - Vascular Endothelium Flashcards
Where do the majority of endothelial cells reside
98% are found in the microvasculature
What is the basic structure of the blood vessels
Tunica adventitia
Tunica media
Tunica Intima
What is in the tunica adventitia
Vasa Vasorum
Nerves
What is in the tunica media
External elastic membrane
Smooth muscle
What is in the tunica intima
Internal elastic membrane
Lamina propria
Basement membrane
Endothelium
Where does the typical blood vessel structure not apply in the vasculature
Venules and capillaries
What’s in the lamina propria
Smooth muscle and connective tissue
What are vasa vasorum
Blood vessels that supply to larger vessels
What do capillaries and venules consist of
Endothelial monolayer with supporting mural cells called pericytes and a surrounding basement membrane
How do we know that endothelial cells contribute to tissue homeostasis
We have seen that endothelial cell damage can lead to dysfunction of the respective organ - therefore it is a source of angiocrine factors that promote tissue homeostasis and organ regeneration
What diseases can a dysfunctional endothelium contribute to
Cancer
Diabetes
Chronic Inflammatory disease
Ischaemia
What is meant by heterogenous endothelial cells
Endothelial cells and microvasculature have organotypic properties and expression profiles relevant to their specific tissue
What are the capillaries of the kidney and liver like
Very permeable to allow for constant transport
(Kidney = fenestrated continuous, Liver = discontinuous)
What are the capillaries of the brain like
Tight blood brain barrier to restrict entry and access to brain
Describe the morphology of endothelial cells
Flat
Large surface area
Form a monolayer
How do endothelial cells form a monolayer
Contact inhibition - junctions form between 2 endothelial cells and this triggers them to stop growing
What cells typically form monolayers
Only endothelial and epithelial cells
Describe the life span or proliferation rate of endothelial cells
Very long lifespan and low proliferation rate unless new blood vessels are needed for angiogenesis
What essential functions of blood vessels are controlled by endothelial cells
Vascular tone Inflammation Permeability Haemostasis and thrombosis Angiogenesis
How do endothelial cells control angiogenesis
Matrix products e.g. proteoglycans
Growth factors e.g. IGF-1
How do endothelial cells control vascular tone and permeability
Vasoconstrictors e.g. ACE
Vasodilators e.g. NO
How do endothelial cells control inflammation
Adhesion molecules e.g. ICAMs
Inflammatory mediators e.g. IL-1
How do endothelial cells control thrombosis and haemostasis
Procoagulants e.g. VWF
Anticoagulants e.g. heparin
What are the properties of resting endothelium
Anti-inflammatory
Anti-thrombotic
Anti-proliferative
What are the properties of active endothelium
Pro-inflammatory
Pro-thrombotic
Pro-proliferative
What is a physiological switch from resting to active endothelium
Occurs in a controlled time and space in order to respond to an event - occurs as part of haemostasis
What causes chronic endothelial activation and what are the effects of this?
(hint - LIST)
When we have chronic activation for example from the triggers for atherosclerosis, we get chronic activation. Over time, this causes thrombosis, senescence, leukocyte recruitment, and increased permeability.
List examples of things that can cause activation of endothelium (SHIVHOM)
Smoking Hypertension Inflammation Viruses High glucose OxLDL Mechanical stress
What is the accepted model form the pathogenesis of atherosclerosis
Response to Injury model
What is the model for atherosclerosis
We get initial injury, this causes endothelial activation and as a result there’s increased permeability, increased leukocyte recruitment and adhesion leading to subsequent transmigration. Transmigration of leukocytes leads to their accumulation in the sub endothelial space - their phagocytosis causes foam cell formation.
As we get more and more advanced, we get more and more macrophage accumulation. They then die and form a necrotic core which forms an inflammatory lesion, and then stimulated angiogenesis from the vasa vasorum in the adventitia
What are the stimuli and risk factors for atherosclerosis
Hypercholesterolaemia Diabetes mellitus/ metabolic syndrome Hypertension Sex hormonal balance Ageing Oxidative stress Proinflammatory cytokines Infectious agents Environmental toxins Haemodynamic forces
O PHISH HEAD
What are the 4 mechanisms contributing to the formation of atherosclerotic plaques
Leukocyte recruitment
Permeability
Shear stress
Angiogenesis
Describe the adhesion cascade
Classical cascade for leukocyte recruitment - endothelium expresses various molecules to prompt response e.g. ICAM.
Cells roll and then find a junction through which they can migrate to work within the tissue during an inflammatory response
What happens to children without a functioning cascade
Die after a few months as they can’t protect themselves from inflammation
Where does physiological leukocyte migration most typically happen
Post-capillary venules - they enter into tissues by squeezing through the cell and chewing up the BM before entering
What is the difference between venule and capillary structure
Venules have more pericytes than capillaries
Where does pathological leukocyte migration happen
Large arteries
What is the problem with leukocyte migration in large arteries
They can’t chew past the various layers of the larger arteries so they get stuck in the sub endothelial space
What is the vascular endothelium
Layer of cells controlling the flux of fluids and molecules in there blood to and from tissues
What is the significance of increased permeability
Increase in plasma proteins leaking through to the sub endothelial space which as sticky ECM and proteoglycans
What is lipoprotein trapping
When the endothelium is activated with increased permeability, we get lipoproteins travelling into the sub endothelial space.
They bind to proteoglycans causing their oxidation.
Macrophages which have also inappropriately migrated into the sub endothelial space will phagocytose the oxidated LDL to form foam cells
Where does atherosclerosis preferentially occur
Bifurcations and curvatures of the vascular tree
Why does atherosclerosis target bifurcations and curvatures
Varying flow pattern and balance of haemodynamic forces along the vasculature
What’s the difference between straight arteries and branches/curvatures
Straight arteries = laminar flow that has a high directional shear stress
Branches/curvatures = disturbed turbulent flow that’s irregularly distributed to give a low wall shear stress
What does laminar flow promote
- Anti-thrombotic factors such as thrombomodulin
- Anti-inflammatory factors
- Endothelial survival
- Inhibition of SMC proliferation
- NO production
What does disturbed or turbulent flow promote
Thrombosis Inflammation Endothelial apoptosis SMC proliferation Loss of NO production
What the role of nitric oxide (6)
Dilates blood vessels Reduces LDL oxidation Reduces superoxide radical release Reduces SMC proliferation Inhibits monocyte adhesion Reduces platelet activation
What is angiogenesis
Formation of new blood vessels sprouting from existing blood vessels
What triggers angiogenesis
Generally hypoxia causes downstream signalling to endothelial cells, this up-regulating factors to initiate angiogenesis through the release of angiogenic factor production
What is angiogenesis involved with
Embryonic development
Menstrual cycle
Wound healing
Also seen in some diseases
What is the janus paradox of angiogenesis in CVD
It has both a beneficial and harmful role in cardiovascular disease
How is angiogenesis good in CVD
We can induce angiogenesis downstream of blocked arteries to prevent damage from ischaemia
How is angiogenesis bad in CVD
lesions become chronic inflammatory diseases of blood vessels to stimulate angiongenesis in the vasa vasorum of the adventitia which contributes to plaque growth
What is the significance of COVID-19 with endothelial activation - how does this present clinically?
There may be a systemic endothelial activation therefore loss of haemostasis due to the presence of local in situ thrombosis in COVID, and how many COVID patients experience both venous and arterial thrombi
What does coagulopathy mean for prognosis
Increase in D-dimer and fibrinogen, and correlates with a poor prognosis
What is recommended for COVID patients at risk from coagulopathy
Anti-thrombotic therapy - under review
What are CEC - how do they relate to anti-thrombotic therapy
Circulating endothelial cells (marker for injury -shed form damage) - found in severe COVID - however anti-coagulation in COVID patients showed a reduction in CEC
What is thrombo-inflammation
Loss of resting endothelium anti-thrombotic/inflammatory properties therefore we get thrombosis associated with inflammation in COVID
When does thromboinflammation occur
COVID and other systemic inflammatory disorders
How does COVID disrupt endothelial function
Bleeding/thrombosis Inflammation Change to permeability Change in vascular tone Change in redox balance
Causes endothelial activation
What are the mechanisms for activation and damage of endothelium with COVID
SARS-CoV2 Infection leads to cytokine storm therefore massive inflammatory reaction. This causes endothelial activation and a consequent procoagulant switch
How does COVID cause direct damage to endothelial cells
2 possible mechanisms:
- Cytokine storm
- SARS-CoV2 enters endothelial cells and causes direct damage
Where is ACE2 expressed
Epithelial cells, not in endothelial cells
Does COVID replicate in endothelial cells?
No
What is the clinical significance of looking at COVID’s role with reference to the endothelium
drugs that reduce endothelial activation may be beneficial in COVID-19 patients however the drug screen is still ongoing
