Cardio - Vascular Endothelium Flashcards
What proportion of endothelial cells make up microvasculature?
98%
What are the 3 general layers of blood vessels?
→ tunica adventitia
→ tunica media
→ tunica intima
What blood vessels are the exceptions to the 3 layer model?
→ capillaries
→ venules
What is the tunica adventitia?
→ outermost layer
→ vasa vasorum, nerves
What is the tunica media?
→ middle layer
→ smooth muscle cells
→ with external elastic membrane
What is the tunica intima?
innermost layer: → internal elastic membrane → lamina propria (smooth muscle and connective tissue → basement membrane → endothelium
What are capillaries + venules made of?
→ formed only by endothelium
→ supported by some mural cells (pericytes)
→ basement membrane
What is the function of capillaries?
→ where the exchanges of nutrients and oxygen between blood and tissues occur
→ Microvascular endothelium promotes tissue homeostasis
How is the microvascular endothelium important in tissue homeostasis?
source of angiocrine factors required for the
maintenance of tissue homeostasis + organ regeneration
What are angiocrine factors?
molecules found in blood vessels’ endothelial cells that can stimulate organ-specific repair activities in damaged or diseased organs
Is all microvasculature the same?
→ NO
→ blood vessels are heterogenic
→ Endothelial cells and microvasculature have organotypic (tissue-specific) properties and expression profiles
What is the function of endothelial cells in the vascular system?
→ acts as a vital barrier separating blood from tissues
→ Very extensive: surface area > 1000 m2; weight >100 g
→ Endothelial cells are very flat, about 1-2 μm thick and 10-20 μm in diameter
→ formed by a monolayer of endothelial cells, one cell deep (contact inhibition)
→ endothelial cells live a long life and have a low proliferation rate (unless new vessels are required: angiogenesis)
→ Endothelial cell regulate essential functions of blood vessels
What functions does the endothelium control?
→ vascular tone → angiogenesis → permeability → inflammation → haemostasis + thrombosis
How does endothelium contribute to angiogenesis?
produces matrix products: → fibronectin → laminin → collagen → proteoglycans → proteases produces growth factors: → insulin like growth factor → transforming growth factor → colony stimulating growth factor
How does endothelium contribute to thrombosis and haemostasis?
produces anti-thrombotic factors: → prostacyclin → thrombomodulin → antithrombin → plasminogen activator → heparin produces pro-coagulant factors: → von Willebrand factor → thromboxane A2 → thromboplastin → Factor V → platelet activating factor → plasminogen activator inhibitor
How does endothelium contribute to vascular tone?
produces vasodilator factors: → nitric oxide → prostacyclin produces vasoconstriction factors: → ACE → thromboxane A2 → leukotrienes → free radicals → endothelin
How does endothelium contribute to inflammation?
adhesion molecules: → ICAMs → VCAM → selectins inflammatory mediators: → interleukins 1, 6, 8 → leukotrienes → MHC II
What is the contact inhibition that endothelium displays?
once in contact with other endothelial cells, cells stop growing and remain 3D
What is the resting state of the endothelium?
by default:
→ anti-thrombotic
→ anti-inflammatory
→ anti-proliferative
What does the activated endothelium state promote?
turned on by tiggers
→ pro-inflammatory
→ pro-angiogenic
→ pro-thrombotic
What are the 3 steps in the pathogenesis of atherosclerosis, in response to injury?
→ endothelial dysfunction
→ fatty-streak formation
→ formation of advanced, complicated lesion
What is involved in endothelial dysfunction?
→ endothelial permeability
→ leukocyte migration
→ endothelial adhesion
→ leukocyte adhesion
What is involved in fatty-streak formation?
→ smooth muscle migration → foam-cell formation → T-cell activation → adherence + aggregation of platelets → adherence + entry of leukocytes
What is involved in the formation of an advanced + complicated lesion?
→ macrophage accumulation
→ formation of necrotic core
→ fibrous-cap formation
→ angiogenesis
What are the stimuli + risk factors for endothelial dysfunction?
→ hypercholesterolaemia (oxidatively modified lipoproteins) → Diabetes Mellitus → Hypertension → Sex hormonal imbalance → Ageing → Oxidative Stress → Proinflammatory Cytokines → Infectious Agents → Environmental Toxins → Haemodynamic forces
What are the 4 mechanisms of endothelial dysfunction?
→ leukocyte recruitment
→ permeability
→ shear stress
→ angiogenesis
What does the leukocyte adhesion cascade involve?
→ capture of leukocyte
→ leukocyte rolls along endothelium, slows then arrests
→ adhesion strengthens + spread, leads to intravascular crawling
→ eventually leads to paracellular or transcellular migration
When + how does leukocyte recruitment occur in venules / capillaries?
→ recruitment normally happens during inflammation
→ leukocytes adhere to endothelium of post-capillary venules + transmigrate to tissues
What is the difference between capillary and post-capillary venules?
similar structure but post-capillary venules contain more pericytes
How does leukocyte recruitment occur in atherosclerosis?
→ leukocytes adhere to activated endothelium of large arteries + get stuck in subendothelial space
→ Monocytes migrate into the subendothelial space, differentiate into macrophages + become foam cells
What are the consequences of increased permeability for endothelium?
leakage of plasma proteins through junctions into endothelial space
How does vascular permeability + leukocyte recruitment lead to foam cell formation?
→ vascular permeability : allows lipoproteins to slip through endothelium into sub-endothelial space
→ leads to being trapped + they bind to proteoglycans, becoming oxidised
→ leukocyte recruitment : recruitment of macrophages causes them to consume oxidised lipoproteins
→ macrophages die + form foam cells
Where do atherosclerosis plaques preferentially form in vasculature?
bifurcations + curvatures in the vascular tree
Why does atherosclerosis occur at particular points in vasculature?
→ flow patterns and hemodynamic forces are not uniform in the vascular system
→ straight parts of the arterial tree = laminar blood flow + wall shear stress is high and directional
→ branches and curvature = blood flow is disturbed with nonuniform and irregular distribution of low wall shear stress
What 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)
- endothelial apoptosis
- SMC proliferation
- Loss of Nitric oxide (NO) production
What are the functions of nitric oxide in the CV system?
→ reduces oxidation of LDL cholesterol → vasodilator → reduces platelet activation → inhibits monocyte adhesion → reduces release of superoxide radicals → reduces proliferation of SMC in vessel wall
What processes is angiogenesis essential for?
→ embryonic development
→ menstrual cycle
→ wound healing
→ therapeutic angiogenesis prevents damage post-ischemia
What are the consequences of angiogenesis?
promotes plaque growth in atherosclerosis
What significance does thrombosis and coagulopathy have in COVID?
- Both venous and arterial thrombi frequent in COVID19 patients
- Incidence unknown; variability in reports and data analysis
- Coagulopathy (increased D-Dimers, Fibrinogen) correlates with poor prognosis
- Anti-thrombotic therapy recommended in all hospitalised patients (recommendation under review)
How does COVID affect coagulapthy?
• COVID infection → cytokine storm → endothelial activation → procoagulant switch
What are the 2 possible mechanisms of COVID affecting endothelial cells?
→ “cytokine storm” secondary to SARS-CoV2 infection causes endothelial damage
→ SARS-CoV2 enters endothelial cells and causes direct damage
