Vascular Endothelium Flashcards
What percentage of endothelial cells are in the microvascular system?
98%
What is the basic structure of blood vessels?
Which 2 blood vessels do not follow this structure?
3 layers:
Tunica adventitia = outermost, vasa vasorum & nerves
Tunica media = middle, smooth muscle cells & external elastic membrane
Tunica intimia = innermost, endothelium & internal elastic membrane
All blood vessels except capillaries and venules
What are vasa vasorum?
Tiny vessels that feed larger vessels
So what is the structure of capillaries and venules?
Capillaries = exchange of nutrients and oxygen between blood and tissues = only by endothelium, supported by some mural cells (pericytes) and a basement membrane
Same in venules
What is the function of the microvascular endothelium?
Promotes tissue homeostasis
Microvascular endothelium = source of angiocrine factors, which is required for tissue homeostasis and organ regeneration
What happens if there is damage to the endothelium?
Contributes to disease more than any other organ in the body
Damaged endothelium = organ dysfunction due to:
Ischemia
Chronic inflammatory diseases
Cancer
Diabetes
How is the microvascular endothelium different between systems?
Endothelial cells and microvasculature have organotypic (tissue-specific) properties and expression profiles
e.g. liver and kidneys = very permeable vasculature due to filtration function compared to brain where there is tight control of what can pass to the brain tissue
What are the 3 types of endothelium and what does it depend on?
Heterogenous - function and phenotype depend on location
Non-fenestrated - muscle, skin, lung, blood brain barrier
Fenestrated - kidney glomerulus
Discontinuous - liver
What are the concepts of the endothelial cells?
Flat cells
Very large surface area
Form a monolayer (one cell deep)
Acts as a vital barrier separating blood from tissues
What is contact inhibition?
Process that takes place when the junction between to cells come together
The establishment of the junction signals the cell to stop growing
What is the lifespan of endothelial cells?
What is the function of endothelial cells?
In vivo, endothelial cells live a long life and have a low proliferation rate (unless new vessels are required = angiogenesis)
Regulate blood vessel function by releasing different factors
What are the multiple functions of blood vessels and what are the factors released by the endothelium to regulate them?
Vascular tone & permeability = vasodilator factors (nitric oxide, prostacyclin) and vasoconstricting factors (ACE, thromboxane A2, leukotrienes, free radicals, endothelin)
Angiogenesis = matrix products (fibronectin, laminin, collagen, proteoglycans, proteases) and growth factors (insulin like growth factor, transforming growth factor, colony stimulating factor)
Inflammation = adhesion molecules (CIAMs, VCAM, selectins) and inflammatory mediators (IL 1, 6, 8, leukotrienes, MHC II)
Haemostasis & Thrombosis = antithrombotic factors (prostacyclin, thrombomodulin, antithrombin, palminogen activator, heparin) and procoagulant factors (von Willebrand factor, thromboxane A2, factor V, platelet activating factor, plasminogen activator inhibitor)
What is the balance of a resting endothelium?
Balance is tipped towards:
Anti-inflammatory
Anti-thrombotic
Anti-proliferative
What pathways are activated when a trigger is present?
Physiological switch to:
Pro-inflammatory
Pro-thrombic
Pro-angiogenic
What can cause chronic activation of the endothelium for the pro-pathway?
Smoking Viruses Mechanical stress Inflammation High blood pressure OxLDL High glucose
What happens when there is chronic activation of the endothelium to the pro-pathway?
Promotes: Thrombosis Senescence Permeability Leukocyte recruitment
Which then all lead to atherosclerosis
What is the pathogenesis of atherosclerosis?
- Initial injury caused by risk factors = endothelial dysfunction: activation of endothelium causes increase in permeability and upregulation of the systems that promote the adhesion of leukocytes
- Leukocytes migrate to the site of dysfunction and adhere to that area, when normally the leukocytes should just flow by.
- This causes leukocyte accumulation in the sub-endothelial space, where phagocytosis of the lipids in the sub-endothelial space leads to foam cell formation AKA fatty streak formation in atherosclerosis
- Eventually, overtime there is the formation of an advanced, complicated lesion of atherosclerosis due to: macrophage accumulation, formation of a neurotic core becoming a chronic inflammatory lesion
What stimuli and risk factors trigger endothelial cell dysfunction in atherosclerosis?
Hypercholesterolaemia
Diabetes Mellitus / metabolic syndrome
Hypertension (e.g. ANG-II, ROS)
Sex hormonal imbalance (e.g. oestrogen deficiency, monpause)
Ageing
Oxidative stress
Proinflammatory cytokines (e.g. IL-1, TNF)
Infectious agents (e.g. bacterial endotoxins, viruses)
Environmental toxins (e.g. smoking, air pollution)
Hemodynamic factors (e.g. disturbed blood flow)
What are the 4 mechanisms in endothelial dysfunction that contribute to the formation of atherosclerotic plaques?
Leukocyte recruitment
Permeability
Shear stress
Angiogenesis
What are the steps of the leukocyte adhesion cascade?
In order to get into a tissue, the leukocytes go through a cascade with the help of the endothelium expressing molecules that support this cascade:
Capture - fall onto endothelial cell
Rolling - along the endothelium
Activation of leukocyte
Arrest of leukocyte
Adhesion - of leukocyte to endothelium
Spreading - leukocyte flattens out
Transmigration - where possible, leukocyte is pushed through endothelial gap to enter interstitial fluid and migrate towards damaged tissue
Where does recruitment into tissues normally take place?
Recruitment of blood leukocytes during inflammation
Leukocytes adhere to the endothelium of post-capillary venules and transmigrate into tissues
How does the structure of a capillary and post-capillary venule differ?
Capillary and post cpillary venule = similar structures
Post capillary venule = more pericytes
Where does recruitment of leukocytes occur in atherosclerosis?
Leukocytes adhere to activated endothelium of large arteries and get stuck in the subendothelial space (as they cannot get past the other 2 layers of the blood vessel wall)
Monocytes migrate into the subendothelial space, differentiate into macrophages and become foam cells
What is the function of the endothelium relating to permeability?
So what is the consequence of increased permeability?
The endothelium regulates the flux of fluids and molecules from blood to tissues and vice versa
Increased permeability results increased flux / leakage of plasma proteins through the junctions into the subendothelial space
What is the process of lipoprotein trapping and oxidative modification that eventually leads to the formation of foam cells?
Inflammed endothelial cells = leaky junctions between them
Lipoproteins (LDLs) manage to leak through the junctions and enter the subendothelial space, which contains proteoglycans
The binding of the lipoproteins and the proteoglycans leads to modifications of the lipoprotein i.e. oxidative modification
The now oxidised lipoprotein (ox-LDL) are engulfed by macrophages (phagocytosis)
Leading to the formation of foam cells
[Foam cells are basically macrophages that have engulfed oxLDL]
Many foam cells = fatty streak formation
Where do atherosclerotic plaques occur preferentially?
Why do they occur preferentially ?
Bifurcations and curvatures of the vascular tree
The flow patterns and haemodynamic forces are not uniform in the vascular system
How does wall shear stress differ between laminar and disturbed blood flow?
In straight parts of the arterial tree, blood flow is laminar and wall shear stress is high and directional
In branches and curvatures, blood flow is disturbed with nonuniform and irregular distribution of low wall shear stress
What does laminar flow promote?
It is protective, and promotes:
Anti-thrombotic, anti-inflammatory factors
Endothelial survival
Inhibition of SMC proliferation
Nitric oxide (NO) production
What does disturbed flow promote?
Disturbed blood flow flips the homeostatic balance by promoting:
Thrombosis, inflammation (leukocyte adhesion)
Endothelial apoptosis
Smooth muscle cell (SMC) proliferation
Loss of Nitric oxide (NO) production
What are the protective effects of nitric oxide on the cardiovascular system?
Dilates blood vessels Reduces platelet activation Inhibits monocyte adhesion Reduces proliferation of SMC in the vessel wall Reduces releases of superoxide radicals Reduces oxidation of LDL cholesterol
What is angiogenesis and what triggers it?
The formation of new vessels by sprouting from existing vessels
Triggered by hypoxia
What are the steps of angiogenesis?
Endothelial cell (EC) receptor binding
EC activation
EC proliferation
Directional migration
ECM remodelling
Tube formation
Loop formation
Vascular stabilisation
What is angiogenesis essential in?
Embryonic development
Wound healing
Menstrual cycles
What are the good and bad outcomes of angiogenesis in cardiovascular disease (CVD)?
Bad = angiogenesis promotes plaque growth
Good = therapeutic angiogenesis prevents damage post-ischaemia
What blood vessel diseases were found frequently COVID-19 patients?
Venous and arterial thrombosis - unknown cause but perhaps due to systemic endothelial activation / loss of endothelial homeostasis (so loss of anti-inflammatory and antithrombotic functions)
What does loss of normal antithrombotic and anti-inflammatory functions cause?
Thrombosis with associated inflammation: thromboinflammation
When do you get thromboinflammation?
Occurs in many disorders, including sepsis, ischemia-reperfusion injury etc.
What does COVID-19 trigger?
Cytokine storm - huge inflammatory reaction, with cytokines, complements, inflammatory cells etc.
Leads to endothelical activation
Procoagulant switch (pro-inflammation, pro-thrombosis)
How can COVID-19 cause endothelial damage?
- By triggering a cytokine storm secondary to the SARS-Cov2 infection
- Or entering the endothelial cells to cause direct damage
Does SARS-CoV2 actually bind endothelial cells?
The main receptor on SARS-Cov2 is ACE2
Lack of evidence where SARS-Cov2 actually binds to endothelial cells as ACE2 is expressed in epithelial cells, not endothelial
What research is ongoing to help COVID-19 and other blood vessel diseases?
Research into drugs that prevent / reduce / reverse endothelial dysfunction are likely to benefit many diseases including COVID-19
